Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：English   Publisher：(公社)日本精神神経学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/pcn5.15

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fnagi.2022.815307

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：(一社)日本総合病院精神医学会  

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

<bold>Background:</bold> The ventral tegmental area (VTA; a dopaminergic nucleus) plays an important role in the sleep-wake regulation system including orexin system. In addition to neuronal activity, there is increasing evidence for an important role of glial cells (i.e., astrocytes and microglia) in these systems. The present study examined the utility of magnetic resonance spectroscopy (MRS) for detecting neural and/or glial changes in the VTA to distinguish responders from non-responders before treatment with the orexin receptor antagonist suvorexant.

<bold>Methods:</bold> A total of 50 patients were screened and 9 patients were excluded. The remaining 41 patients with insomnia who have or not a psychiatric disease who were expected to receive suvorexant treatment were included in this study. We compared MRS signals in the VTA between responders to suvorexant and non-responders before suvorexant use. Based on previous reports, suvorexant responders were defined as patients who improved ≥3 points on the Pittsburgh Sleep Quality Index after 4 weeks of suvorexant use. MRS data included choline (reflects non-specific cell membrane breakdown, including of glial cells) and N-acetylaspartate (a decrease reflects neuronal degeneration).

<bold>Results:</bold> Among 41 examined patients, 20 patients responded to suvorexant and 21 patients did not. By MRS, the choline/creatine and phosphorylcreatine ratio in the VTA was significantly high in non-responders compared with responders (<italic>p</italic> = 0.039) before suvorexant treatment. There was no difference in the N-acetylaspartate/creatine and phosphorylcreatine ratio (<italic>p</italic> = 0.297) between the two groups.

<bold>Conclusions:</bold> Changes in glial viability in the VTA might be used to distinguish responders to suvorexant from non-responders before starting treatment. These findings may help with more appropriate selection of patients for suvorexant treatment in clinical practice. Further, we provide novel possible evidence for a relationship between glial changes in the VTA and the orexin system, which may aid in the development of new hypnotics focusing on the VTA and/or glial cells.

DOI： 10.3389/fpsyt.2021.714376

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Early diagnosis of individuals' at-risk mental state (ARMS) is important for preventing their pathogenesis or, at least, delaying onset of overt psychosis. Traditional diagnosis of ARMS subjects is mainly based on structured interviews, but future diagnosis would be carried out together with biomarkers. AIM: In this study, we report urinary biopyrrins and free immunoglobin light chains κ and λ (κFLC and λFLC) as novel diagnostic biomarker candidates for screening ARMS subjects. METHODS: Nineteen ARMS subjects and 21 age- and sex-matched healthy controls were enrolled in this study. Inclusion criteria of the ARMS subjects were based on a comprehensive assessment of Structured Interview for Prodromal Syndromes. We compared oxidative stress and immunological markers in the urine of ARMS subjects with those of healthy controls by ELISA protocol. RESULTS: Augmentation of biopyrrins and reduction of κFLC and λFLC were found in the ARMS samples, and their diagnostic performance was evaluated by receiver operating characteristic analysis, of which area under the curve was as large as 0.915 in combination. CONCLUSION: Our findings suggest that the ARMS subjects were under higher oxidative stress but lower in B cell activation, and that the combined assay of urinary biopyrrins and free immunoglobulin light chains would be useful for the early detection and screening of ARMS subjects among adolescents.

DOI： 10.1111/eip.13154

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DOI： 10.4088/JCP.20lr13818a

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.sleep.2021.01.030

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BACKGROUND: Severe neonatal hyperbilirubinemia has been known to cause the clinical syndrome of kernicterus and a milder one the syndrome of bilirubin-induced neurologic dysfunction (BIND). BIND clinically manifests itself after the neonatal period as developmental delay, cognitive impairment, and related behavioral and psychiatric disorders. The complete picture of BIND is not clear. METHODS: The Gunn rat is a mutant strain of the Wistar rat with the BIND phenotype, and it demonstrates abnormal behavior. We investigated serotonergic dysfunction in Gunn rats by pharmacological analyses and ex vivo neurochemical analyses. RESULTS: Ketanserin, the 5-HT2AR antagonist, normalizes hyperlocomotion of Gunn rats. Both serotonin and its metabolites in the frontal cortex of Gunn rats were higher in concentrations than in control Wistar rats. The 5-HT2AR mRNA expression was downregulated without alteration of the protein abundance in the Gunn rat frontal cortex. The TPH2 protein level in the Gunn rat raphe region was significantly higher than that in the Wistar rat. CONCLUSIONS: It would be of value to be able to postulate that a therapeutic strategy for BIND disorders would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after onset of BIND manifestations. IMPACT: We demonstrated serotonergic dysregulation underlying hyperlocomotion in Gunn rats. This finding suggests that a therapeutic strategy for bilirubin-induced neurologic dysfunction (BIND) would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after the onset of the BIND manifestations. Ketanserin normalizes hyperlocomotion of Gunn rats. To our knowledge, this is the first study to demonstrate a hyperlocomotion link to serotonergic dysregulation in Gunn rats.

DOI： 10.1038/s41390-021-01446-1

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INTRODUCTION: Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone (PTH). PHPT presents with a complex set of renal, skeletal, and neuropsychological symptoms. Parathyroidectomy (PTX) is a radical treatment that is recommended for all physically symptomatic patients with PHPT. However, psychiatric symptoms are not considered as an indication for surgery. There remains an important issue from the view of perioperative management of whether PTX should be performed with the presence of uncontrolled psychiatric symptoms or deferred until severe psychiatric symptoms have been controlled. We report a case of mild hypercalcemia that caused severe psychosis in PHPT, which improved dramatically following PTX and resulted in successful postoperative management. PATIENT CONCERN: Our patient was a 68-year-old Japanese woman. She was diagnosed with PHPT, which was triggered by mild hypercalcemia. She was due to receive an operation for osteoporosis and kidney stones. She had severe psychosis, despite medication. Blood examinations revealed mild hypercalcemia (10.4 mg/dL, 8.8-10.1 mg/dL) and elevated serum levels of intact PTH (184.0 pg/mL, 10-65 pg/mL). DIAGNOSIS: She was diagnosed with severe psychosis caused by mild hypercalcemia in PHPT. INTERVENTIONS: Although she was treated with 37.5 mg quetiapine and 2 mg risperidone daily, she was excessively sedated and rejected oral treatment. Therefore, we decided to perform the operation. OUTCOMES: Immediately following surgery, serum levels of calcium, and intact PTH were normalized. Her psychotic symptoms ceased completely 5 days after surgery. CONCLUSION: We emphasize that PHPT presents with various severe psychiatric symptoms, even in mild hypercalcemia. Psychiatric symptoms may be the only salient symptoms in PHPT, and thus clinicians should suspect PHPT in patients with psychiatric symptoms and mild hypercalcemia. Furthermore, PTX is recommended for PHPT-even in the presence of severe uncontrolled psychiatric symptoms, which carries risks for postoperative management-because psychiatric symptoms are expected to improve and good postoperative management is possible.

DOI： 10.1097/MD.0000000000025248

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DOI： 10.5603/IMH.2021.0024

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

DOI： 10.3389/fnagi.2020.589196

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：Japanese   Publisher：(株)ワールドプランニング  

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The neuroinflammatory hypothesis of Alzheimer's disease (AD) was proposed more than 30 years ago. The involvement of the two main types of glial cells, microglia and astrocytes, in neuroinflammation was suggested early on. In this review we highlight that the exact contributions of reactive glia to AD pathogenesis remain difficult to define likely due to the heterogeneity of glia populations and alterations in their activation states through the stages of AD progression. In the case of microglia, it is becoming apparent that both beneficially and adversely activated cell populations can be identified at various stages of AD, which could be selectively targeted to either limit their damaging actions or enhance beneficial functions. In the case of astrocytes, less information is available about potential subpopulations of reactive cells; it also remains elusive whether astrocytes contribute to the neuropathology of AD by mainly gaining neurotoxic functions or losing their ability to support neurons due to astrocyte damage. We identify L-type calcium channel blocker, nimodipine, as a candidate drug for AD, which potentially targets both astrocytes and microglia. It has already shown consistent beneficial effects in basic experimental and clinical studies. We also highlight the recent evidence linking peripheral inflammation and neuroinflammation. Several chronic systemic inflammatory diseases, such as obesity, type 2 diabetes mellitus, and periodontitis, can cause immune priming or adverse activation of glia thus exacerbating neuroinflammation and increasing risk or facilitating progression of AD. Therefore, reducing peripheral inflammation is a potentially effective strategy for lowering AD prevalence.

DOI： 10.2174/1570159X18666201111104509

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© 2020 Elsevier B.V. In Japan over the past few years, approximately 13,000 individuals were arrested for drug offenses each year. It is useful to know the trends in drug offenses, in order to devise the most effective countermeasures and addiction treatment programs. Herein, we have revealed the trends in drug offenses in the Tokyo Metropolitan Area. This report was researched the number of individuals arrested for drug offenses in Tokyo during the 3-year study period 2016–2018. The drugs are classified into the six categories: stimulants, narcotics, psychoactive drugs, opium, cannabis, and designated substances. We also calculated the percentages of individuals arrested for various drug offenses based on these six categories. Approximately 86% of the arrests for drug offenses in Tokyo during the 3-year period were for stimulants or cannabis. A higher percentage of individuals were arrested for stimulants, but the percentage of individuals arrested for cannabis increased each year. Given the percentage of individuals arrested for designated substances or narcotics, preventive measures for drug offenses involving stimulants and cannabis should be promptly implemented. Further campaigns to prevent drug offenses and public lectures are also needed. Public education must be provided to prevent drug offenses involving designated substances and narcotics.

DOI： 10.1016/j.legalmed.2020.101739

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© Copyright 2020 Physicians Postgraduate Press, Inc. OBJECTIVE: This study aimed to examine the effects of suvorexant on delirium prevention in a real-world setting. Previous studies have demonstrated the efficacy of suvorexant for delirium prevention in limited randomized clinical trial settings; however, its effectiveness in everyday clinical settings remains unknown. METHODS: A single-center, retrospective cohort study was conducted in the intensive care unit of an academic hospital. Patients (aged ≥ 3 years) admitted from January 2016 to December 2018 were eligible if they stayed in the intensive care unit for at least 72 hours. Suvorexant was prescribed by the attending physician for insomnia as part of everyday clinical practice. A Cox proportional hazards regression analysis was conducted on delirium-free survival for suvorexant users, adjusting for delirium-related covariates. As part of routine clinical practice, the Confusion Assessment Method for the Intensive Care Unit was used to detect the existence of delirium at least twice daily throughout the intensive care unit stay. RESULTS: There were 699 patients-84 suvorexant users and 615 suvorexant nonusers. Delirium was detected in 214 patients. Delirium prevalence was significantly lower in suvorexant users than in nonusers (17.9% vs 32.4%, respectively; P = .007). Cox regression analysis revealed a significantly lower hazard ratio (0.472; 95% CI, 0.268-0.832; P = .009) of delirium in suvorexant users than in nonusers. Trazodone also had a preventive effect on delirium (hazard ratio 0.345; 95% CI, 0.149-0.802; P = .013). CONCLUSIONS: The present study extends to real-world settings previous findings that suvorexant is effective for delirium prevention.

DOI： 10.4088/JCP.20m13362

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DOI： 10.2174/1871527319666200905142503

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DOI： 10.1177/1010539520940893

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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DOI： 10.1177/0025802420917063

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：(一社)日本心身医学会  

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Language：Japanese   Publisher：(一社)日本心身医学会  

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DOI： 10.1111/psyg.12465

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The growing demands have been placed on nurses working in public healthcare system, mostly due to expanding set of required competence. The presented cross-sectional study is aimed to investigate the level of self-assessed competence of community nurses in three primary health care establishments of Kazakhstan and to identify the relatives' perception of competence needed to provide medical care to their severely ill family members. The subjects enrolled into the study were 115 nurses employed in three primary healthcare establishments of Kazakhstan and 58 relatives/caregivers registered at the same establishments. Stoma care appeared to be the most problematic task for nurses in addition to providing of the first aid in different emergency situations, such as dyspnea, cardiac pain, vomiting, and pain attack. Relatives/caregivers reported satisfactory levels of such competence as feeding a bedridden patient, maintenance of basic hygiene, performing a simple physical therapy and instillation of eye/ear drops. Our results could be useful for healthcare managers in obtaining a clear vision of which educational areas require prioritization and guide public health interventions to overcome the identified problems.

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© 2020 Bentham Science Publishers. Background: Fibroblast Growth Factor (FGF) 2 (also referred to as basic FGF) is a multi-functional growth factor that plays a pivotal role in the pro-survival, pro-migration and pro-differentiation of neurons. Method: Because alterations in FGF2 levels are suggested to contribute to the pathogenesis of schizo-phrenia, we investigated serum levels of FGF2 in the Gunn rat, a hyperbilirubinemia animal model of schizophrenic symptoms. Results: The enzyme-linked immunosorbent assay showed that the serum levels of FGF2 in Gunn rats were 5.09 ± 0.236 pg/mL, while those in the normal strain Wistar rats, serum levels were 11.90 ± 2.142 pg/mL. The serum FGF2 levels in Gunn rats were significantly lower than those in Wistar rats. We also measured serum levels of Unconjugated Bilirubin (UCB) and found a significant negative correlation between UCB and FGF2 in terms of serum levels in all the rats studied. Conclusion: Since it is known that FGF2 regulates dopaminergic neurons and have anti-neuroinflammatory effects, our finding suggests that low FGF2 levels may contribute to the pathogen-esis of schizophrenia, in which imbalanced dopamin-ergic signaling and neuroinflammation are sup-posed to play certain roles.

DOI： 10.2174/1871527319999200729153907

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DOI： 10.5603/IMH.2020.0039

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© 2019 Japan Health Sciences University & Japan International Cultural Exchange Foundation. Background: The Japanese suicide rate has decreased over the past few years, but the rate still remains high in comparison to the rest of the world. Thus, Japan cannot be content with implementing current suicide prevention measures; additional suicide prevention measures should be devised. Materials and Methods: We compared suicide rates among sex and age groups in Japan and Hungary, both of which have a high suicide rate. We focused on individuals overall and on individuals ages 5-14, 15-24, and 25-34 years. Based on the results of our analyses, we discuss suicide prevention measures for Japanese individuals in this age range. Results: Hungary has a somewhat higher overall suicide rate among males than Japan. The overall suicide rate among females is high in both Japan and Hungary, but Japan has a higher suicide rate among both males and females ages 5-14, 15-24, and 25-34. Conclusion: Japanese suicide prevention measures targeting younger generations must be devised. Preventive measures need to be examined from various perspectives and implemented.

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© 2019 Background: Although growing evidence indicates that ECT affects astrocytes, the exact mechanisms of the therapeutic effect of ECT are still unknown. Astrocytic endfeet express the water channel aquaporin (AQP) 4 abundantly and ensheath brain blood vessels to form gliovascular units. It has been shown that the coverage of blood vessels by AQP4-immunostained endfeet is decreased in the prefrontal cortex (PFC) of patients with major depression. This study was made to determine whether ECT restores the astrocytic coverage of blood vessels with amelioration of depressive symptoms. Methods: After electroconvulsive shock (ECS) administration to rats, the forced swimming test (FST) and Y-maze test were performed. Subsequently, immunofluorescence analysis was conducted to measure the coverage of blood vessels by astrocytic endfeet in the PFC and hippocampus by using the endothelial cell marker lectin and anti-AQP4 antibody. We also performed Western blot to examine the effects of ECS on the hippocampal expression of AQP4 and the tight junction molecule claudin-5. Results: Gunn rats showed learned helplessness and impaired spatial working memory, compared to normal control Wistar rats. ECS significantly improved the depressive-like behavior. Gunn rats showed a decrease in astrocytic coverage of blood vessels, that was significantly increased by ECS. ECS significantly increased expression of AQP4 and claudin-5 in Gunn rats. Conclusions: ECS increased the reduced coverage of blood vessels by astrocytic endfeet in the mPFC and hippocampus with amelioration of depressive-like behavior. Therefore, therapeutic mechanism of ECT may involve restoration of the impaired gliovascular units by increasing the astrocytic-endfoot coverage of blood vessels.

DOI： 10.1016/j.jad.2019.07.008

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DOI： 10.1177/1010539519867220

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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Increasing evidence implies a possible causal link between periodontitis and neuropsychiatric disorders, such as Alzheimer’s disease (AD) and major depression (MD). A possible mechanism underlying such a link can be explained by neuroinflammation induced by chronic systemic inflammation. This review article focuses on an overview of the biological and epidemiological evidence for a feasible causal link of periodontitis to neuropsychiatric disorders, including AD, MD, Parkinson’s disease, and schizophrenia, as well as the neurological event, ischemic stroke. If there is such a link, a broad spectrum of neuropsychiatric disorders associated with neuroinflammation could be preventable and modifiable by simple daily dealings for oral hygiene. However, the notion that periodontitis is a risk factor for neuropsychiatric disorders remains to be effectively substantiated.

DOI： 10.3390/ijms20153723

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© 2019 A reduction of GABAergic markers in postmortem tissue is consistently found in schizophrenia. Importantly, these alterations in GABAergic neurons are not global, which means they are more prevalent among distinct subclasses of interneurons, including those that express the calcium binding protein parvalbumin. A decreased expression of parvalbumin in the hippocampus is a consistent observation not only in postmortem human schizophrenia patients, but also in a diverse number of rodent models of the disease. Meanwhile, previously we reported that the congenital hyperbilirubinemia model rats (Gunn rats), which is a mutant of the Wistar strain, showed behavioral abnormalities, for instance, hyperlocomotor activity, deficits of prepulse inhibition, inappropriate social interaction, impaired recognition memory similar with several rodent models of schizophrenia. Several animal studies linked the importance of palvalbumin in relation to abnormal hippocampal activity and schizophrenia-like behavior. Here, we show that parvalbumin positive cell density was significantly lower in the CA1, CA3 and the total hippocampus of Gunn rats (congenital hyperbilirubinemia model rats) compared to Wistar control rats. The correlations between serum UCB levels and loss of PV expression in the hippocampus were also detected. The decreases in the PV-expression in the hippocampus might suggest an association of the behavioral abnormalities as schizophrenia-like behaviors of Gunn rats, compared to the Wistar control rats.

DOI： 10.1016/j.heliyon.2019.e02037

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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DOI： 10.1177/1010539519844079

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Language：Japanese   Publisher：(一社)日本総合病院精神医学会  

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© 2019 Misako Kanayama et al. Relationships between gut microbiota and various disease pathogeneses have been investigated, but those between the pathogeneses of mental illnesses, including schizophrenia, and gut microbiota have only recently attracted attention. We observed a change in the gut microbiota of a patient with schizophrenia after administering electroconvulsive therapy (ECT). A 59-year-old woman was diagnosed with schizophrenia at 17 years of age and has been taking antipsychotic drugs since the diagnosis. Clostridium, which occupied 86.5% of her bacterial flora, decreased to 72.5% after 14 ECT sessions, while Lactobacillus increased from 1.2% to 5.5%, and Bacteroides increased from 9.1% to 31.5%. Previous studies have shown that Clostridium spp. are increased in patients with schizophrenia compared with those in healthy individuals and that Clostridium is reduced after pharmacological treatment. Our report is the first report on the gut microbiota of a patient with schizophrenia receiving ECT. Our results indicate that studies focusing on Clostridium to clarify the pathogenesis of schizophrenia as well as potential therapeutic mechanisms may be beneficial. However, further studies are needed.

DOI： 10.1155/2019/4576842

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© 2019 Japan Health Sciences University & Japan International Cultural Exchange Foundation. Background: Japan has experienced many large earthquakes. In fact Japan is considered one of the most earthquake-prone countries in the world. A large quake occurred on June 18, 2018, in northern Osaka Prefecture. Osaka Prefecture is one of Japan's larger prefectures, and this earthquake highlighted the issue of urban earthquakes. Materials and Methods: Here, we describe events that transpired during the northern Osaka Prefecture Earthquake. Based on what happened, we also discuss future measures for dealing with urban earthquakes. Results: We found that the earthquake revealed important measures that are needed during the initial and intermediate response to future urban earthquakes. Conclusion: We concluded that government agencies, the medical establishment, transportation services, other entities, and the public must consider and work together to implement measures to deal with urban earthquakes.

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© 2019 Tohoku University Medical Press. Problematic smartphone use among adolescents has become a social concern and is associated with poor sleep quality. The relationship between life habits, such as smartphone use and sleep duration, and levels of immunological and neuroendocrine biomarkers, including the stress hormone cortisol, in adolescents seems to be important to objectively comprehend their health and well-being in school life. However, such a relationship has not been well documented. We therefore studied rural junior high school students in Japan to elucidate the relationship between serum cortisol (SC) levels and their life habits. A total of 155 students in the seventh grade in 2016 were recruited as subjects. Of them, 140 students with eligible responses and blood samples (12-13 years; 80 boys, 60 girls) were finally included in the study (response rate 90.3%). A questionnaire survey concerning wake-up time, sleep duration, and the length of time using a smartphone per day was conducted. Blood samples were collected from peripheral veins of participants under fasting conditions between 8:30 and 11:00 a.m. The Spearman rank correlation coefficients were as follows: Between SC and wake-up time, 0.199 (p = 0.018); between SC and sleep duration, 0.185 (p = 0.029); and between SC and time spent on smartphones, 0.172 (p = 0.042). The multiple regression analysis showed that high SC levels were significantly associated with late wake-up time and with short sleep duration. We therefore propose that measuring SC levels is useful for early detection of the change in the well-regulated daily life among junior high school students.

DOI： 10.1620/tjem.249.143

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© Wolters Kluwer Health, Inc. All rights reserved. Aim Up to 60% of depressed patients do not obtain sufficient relief from a course of antidepressant therapy, and these treatment-resistant major depressive disorder (TRD) patients are at increased risk for relapse, chronicity, persistent psychosocial impairments, and suicide. Probiotics actively participate in treatment of neuropsychiatric disorders. However, the role of gut microbiota in brain disorders and depression remains unclear. We performed a prospective study to evaluate the effects of Clostridium butyricum MIYAIRI 588 (CBM588). Methods This was an 8-week open-label study to evaluate the efficacy and safety of CBM588 in combination with antidepressants in adult patients diagnosed with TRD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Forty antidepressant-treated inpatients were included. Patients were randomized to adjuvant treatment with CBM588 (n = 20) or control (n = 20). The primary endpoint was the change in the 17-item Hamilton Depression Rating Scale score from baseline to week 8. Secondary end points were changes in the Beck Depression Inventory and the Beck Anxiety Inventory scale scores from baseline to week 8. The Systematic Assessment of Treatment Emergent Events - General Inquiry was used to assess adverse effects. Results CBM588 (60 mg/d) in combination with antidepressants (flvoxamine, paroxetine, escitalopram, duroxetine, and sertraline) provided significant improvement in depression. All patients completed the trial, and 70% responded to treatment; the remission rate was 35.0%. No serious adverse events occurred. Conclusions These preliminary data suggest that CBM588 in combination with antidepressants is effective and well tolerated in the treatment of TRD. Further studies using a larger, double-blind, parallel-group design are warranted to confirm these findings.

DOI： 10.1097/WNF.0000000000000299

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© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. Introduction: Recent studies imply that glial activation plays a role in the pathogenesis of psychiatric disorders, such as schizophrenia and major depression. We previously demonstrated that Gunn rats with hyperbilirubinemia show congenital gliosis and schizophrenia-like behavior. Methods: As it has been suggested that major depression involves glial activation associated with neuroinflammation, we examined whether Gunn rats show depression-like behavior using the forced swimming test (FST) and the tail suspension test (TST). In addition, we quantitatively evaluated both microgliosis and astrogliosis in the hippocampus of Gunn rats using immunohistochemistry analysis of the microglial marker ionized calcium-binding adaptor molecule (Iba) 1 and the astrocytic marker S100B. Results: Both the FST and TST showed that immobility time of Gunn rats was significantly longer than that of normal control Wistar rats, indicating that Gunn rats are somewhat helpless, a sign of depression-like behavior. In the quantification of immunohistochemical analysis, Iba1immunoreactivity in the dentate gyrus (DG), cornu ammonis (CA) 1, and CA3 and the number of Iba1-positive cells in the CA1 and CA3 were significantly increased in Gunn rats compared to Wistar rats. S100B immunoreactivity in the DG, CA1, and CA3 and the number of S100B-positive cells in the DG and CA3 were significantly increased in Gunn rats compared to Wistar rats. Conclusion: Our findings suggest that both microglia and astrocyte are activated in Gunn rats and their learned helplessness could be related to glial activation.

DOI： 10.1002/brb3.1028

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© 2018 Hashioka, Inoue, Hayashida, Wake, Oh-Nishi and Miyaoka. Increasing evidence suggests that infection and persistent low-grade inflammation in peripheral tissues are important pathogenic factors in major depression. Major depression is frequently comorbid with systemic inflammatory diseases/conditions such as rheumatoid arthritis, allergies of different types, multiple sclerosis, cardiovascular disease, inflammatory bowel disease, chronic liver disease, diabetes, and cancer, in which pro-inflammatory cytokines are overexpressed. A number of animal studies demonstrate that systemic inflammation induced by peripheral administration of lipopolysaccharide increases the expression of pro-inflammatory cytokines in both the periphery and brain and causes abnormal behavior similar to major depression. Systemic inflammation can cause an increase in CNS levels of pro-inflammatory cytokines associated with glial activation, namely, neuroinflammation, through several postulated pathways. Such neuroinflammation can in turn induce depressive moods and behavioral changes by affecting brain functions relevant to major depression, especially neurotransmitter metabolism. Although various clinical studies imply a causal relationship between periodontitis, which is one of the most common chronic inflammatory disorders in adults, and major depression, the notion that periodontitis is a risk factor for major depression is still unproven. Additional population-based cohort studies or prospective clinical studies on the relationship between periodontitis and major depression are needed to substantiate the causal link of periodontitis to major depression. If such a link is established, periodontitis may be a modifiable risk factor for major depression by simple preventive oral treatment.

DOI： 10.3389/fnins.2018.00483

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© 2018 Izuhara, Matsuda, Saito, Hayashida, Miura, Oh-Nishi, Azis, Abdullah, Tsuchie, Araki, Ryousuke, Kanayama, Hashioka, Wake, Miyaoka and Horiguchi. The authors present the case of a 38-year-old man with schizophrenia and with severe insomnia, who attempted suicide twice during oral drug therapy with risperidone. The patient slept barely 2 or 3 h per night, and he frequently took half days offfrom work due to excessive daytime sleepiness. As a maladaptive behavior to insomnia, he progressively spent more time lying in bed without sleeping, and he repeatedly thought about his memories, which were reconstructed from his hallucinations. His relatives and friends frequently noticed that his memories were not correct. Consequently, the patient did not trust his memory, and he began to think that the hallucinations controlled his life. During his insomniac state, he did not take antipsychotic drugs regularly because of his irregular meal schedule due to his excessive daytime sleepiness. The authors started cognitive behavioral therapy for insomnia (CBT-i) with aripiprazole long acting injection (LAI). CBT-i is needed to be tailored to the patient's specific problems, as this case showed that the patient maladaptively use chlorpromazine as a painkiller, and he exercised in the middle of the night because he believed he can fall asleep soon after the exercise. During his CBT-i course, he learned how to evaluate and control his sleep. The patient, who originally wanted to be short sleeper, began to understand that adequate amounts of sleep would contribute to his quality of life. He finally stopped taking chlorpromazine and benzodiazepine as sleeping drugs while taking suvorexant 20 mg. Through CBT-i, he came to understand that poor sleep worsened his hallucinations, and consequently made his life miserable. He understood that good sleep eased his hallucinations, ameliorated his daytime sleepiness and improved his concentration during working hours. Thus, he was able to improve his self-esteem and self-efficacy by controlling his sleep. In this case report, the authors suggest that CBT-i can be an effective therapy for schizophrenia patients with insomnia to the same extent of other psychiatric and non-psychiatric patients.

DOI： 10.3389/fpsyt.2018.00260

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：English   Publisher：(公社)日本精神神経学会  

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Language：English   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Copyright © 2018 Misako Kanayama et al. Background. Dysfunction of the autonomic nervous system (ANS) in schizophrenia has been detected by electrophysiological methods, but the underlying mechanisms remain unknown. Several studies have suggested that measuring salivary alpha-amylase activity levels is useful for evaluating the ANS activity and that sAA levels increase in schizophrenia and correlate with Brief Psychiatric Rating Scale (BPRS) scores. However, no study has examined the relationship between sAA activity levels and symptoms of schizophrenia with catatonic state. Methods. We present the case of a 59-year-old female with persistent catatonic schizophrenia treated by electroconvulsive therapy. We evaluated the ANS activity by measuring sAA activity levels before and after ECT, and we evaluated her symptoms using the BPRS and Bush-Francis Catatonia Rating Scale (BFCRS). Results. ECT was highly effective and BPRS and BFCRS scores substantially decreased. sAA activity levels decreased from 125 kU/l to 33 kU/l. Conclusions. sAA activity levels could be a potential biomarker of schizophrenia with catatonic state.

DOI： 10.1155/2018/2623585

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Publishing type：Research paper (scientific journal)   Publisher：OMICS Publishing Group  

DOI： 10.4172/neuropsychiatry.1000421

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© 2017 Miyaoka, Wake, Hashioka, Hayashida, Oh-Nishi, Azis, Izuhara, Tsuchie, Araki, Arauchi, Abdullah and Horiguchi. The authors present the case of a 24-year-old male with treatment-resistant schizophrenia, with predominant severe delusion and hallucination, who received bone marrow transplantation (BMT) for acute myeloid leukemia. After BMT, he showed a remarkable reduction in psychotic symptoms without administration of neuroleptics. He also showed drastic improvement in social functioning. Follow-up evaluations 2 and 4 years after BMT showed persistent significant improvement of the psychotic state and social functioning. Recent findings show that the major underlying pathogenic mechanism of schizophrenia is immune dysregulation. Thus, conceptually, BMT, a cellular therapy, that facilitates the counteractive processes of balancing inflammation by immune regulation, could produce beneficial clinical effects in patients with treatment-resistant schizophrenia. Further studies are required to define the true benefits of BMT for the possible curative treatment of schizophrenia.

DOI： 10.3389/fpsyt.2017.00174

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DOI： 10.4172/neuropsychiatry.1000192

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© 2016 The Author(s). Background: Although electroconvulsive therapy (ECT) is regarded as one of the efficient treatments for intractable psychiatric disorders, the mechanism of therapeutic action remains unclear. Recently, many studies indicate that ECT affects the immune-related cells, such as microglia, astrocytes, and lymphocytes. Moreover, microglial activation and astrocytic activation have been implicated in the postmortem brains of schizophrenia patients. We previously demonstrated that Gunn rats showed schizophrenia-like behavior and microglial activation in their brains. The present study examined the effects of electroconvulsive shock (ECS), an animal counterpart of ECT, on schizophrenia-like behavior, microgliosis, and astrogliosis in the brain of Gunn rats. Methods: The rats were divided into four groups, i.e., Wistar sham, Wistar ECS, Gunn sham, and Gunn ECS. ECS groups received ECS once daily for six consecutive days. Subsequently, prepulse inhibition (PPI) test was performed, and immunohistochemistry analysis was carried out to determine the activation degree of microglia and astrocytes in the hippocampus by using anti-CD11b and anti-glial fibrillary acidic protein (GFAP) antibody, respectively. Results: We found PPI deficit in Gunn rats compared to Wistar rats, and it was significantly improved by ECS. Immunohistochemistry analysis revealed that immunoreactivity of CD11b and GFAP was significantly increased in Gunn rats compared to Wistar rats. ECS significantly attenuated the immunoreactivity of both CD11b and GFAP in Gunn rats. Conclusions: ECS ameliorated schizophrenia-like behavior of Gunn rats and attenuated microgliosis and astrogliosis in the hippocampus of Gunn rats. Accordingly, therapeutic effects of ECT may be exerted, at least in part, by inhibition of glial activation. These results may provide crucial information to elucidate the role of activated glia in the pathogenesis of schizophrenia and to determine whether future therapeutic interventions should attempt to up-regulate or down-regulate glial functions.

DOI： 10.1186/s12974-016-0688-2

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Language：English   Publisher：OXFORD UNIV PRESS  

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Language：English   Publisher：OXFORD UNIV PRESS  

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Language：English   Publisher：OXFORD UNIV PRESS  

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Language：English   Publisher：OXFORD UNIV PRESS  

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Language：English   Publisher：OXFORD UNIV PRESS  

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© 2016 Bentham Science Publishers. A neuropsychiatric syndrome, Autism spectrum disorder (ASD) is qualified via impairments in qualitative communication, social interaction, and stereotyped or restricted, repetitive patterns of behavior, interests, or activities. While all ASDs are considered to have qualitative deficits in social relatedness to others, many people with ASDs have other symptoms, including irritability (which includes aggression, self-injurious behavior, and severe tantrums). In order to decrease these behaviors, it is often helpful to make use of behavioral therapy. In addition, due to the intensity and severity of irritability, adjunctive medications are sometimes needed. Although many of the adjunctive medications have been tested and demonstrated to be useful in treating ASD, no clear standardized treatment has emerged. While the adjunctive medications have shown efficacy, the associated side effects have proven to be a barrier to their accepted use. A traditional Japanese medicine, Yokukansan (YKS), is composed of seven kinds of dried herbs and is widely clinically prescribed for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous systems. YKS may be safe and useful in treating dementia patients’ behavioral and psychological symptoms according to indications from recent studies. We introduce in this review, the ameliorative effects of YKS on Asperger's disorder in open-label studies and on ASDs including pervasive developmental disorder not otherwise specified (PDD-NOS). This review will suggest that YKS is well tolerated and effective for the treatment for subjects with ASD who have severe hyperactivity/noncompliance and irritability/agitation. Additionally, the serotonergic, glutamatergic, anti-inflammatory and neurogenesis effects are explored which are thought to be involved in the mechanisms underlying the efficacy of YKS.

DOI： 10.2174/1871527315666160413120541

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© 2015, Springer-Verlag Berlin Heidelberg. Progressive disability in schizophrenia has been considered to be associated with onset-age. The objective of this study was to evaluate age onset-related degeneration in rCBF in patients with schizophrenia. We evaluated characteristic changes in brain perfusion by age, gender, medication and clinical symptoms in medicated patients with early-onset (EOS: developed at younger than 40 years old: n = 44) and late-onset (LOS: developed at older than 40 years old: n = 19) schizophrenia and control subjects matched for age and gender (n = 37) using statistical parametric mapping (SPM8) applied to 99mTc-ECD SPECT. We performed SPECT with 99mTc-ECD on the brains of subjects. A voxel-by-voxel group analysis was performed using SPM 8 and ANOVA. rCBF in EOS was found to be reduced in the precentral and inferior frontal gyri; on the other hand, rCBF was reduced in the bilateral postcentral gyrus in LOS. This study revealed a significant difference in brain perfusion between EOS and LOS. The present study might suggest that the characteristic changes in rCBF are related to onset-age in schizophrenia.

DOI： 10.1007/s00406-015-0607-z

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Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by mutations in the ceruloplasmin gene. Its prevalence is 1 in 2,000,000 people in Japan. This is a disorder of neurodegeneration with iron accumulation in the brain revealed by MRI. The iron overload induces oxidative stress and generation of reactive oxygen species, which triggers a cascade of pathological events that lead to neuronal death. Intravenous administration of an iron chelator, deferoxamine has been proposed as a method of inhibiting the accumulation of iron. The patient was a 46-year-old Japanese woman. She was diagnosed at the age of 33 years. Deferoxamine was administrated for 6 months but was discontinued due to adverse effects. On admission at the age of 46, psychomotor excitement was acute in onset. The extrapyramidal symptoms reflected iron deposition in the basal ganglia and substantia nigra in the midbrain. Ataxia and a wide-based gate reflected iron deposition in the dentate nuclei of the cerebellum. An antibiotic, minocycline at 150 mg/day successfully ameliorated the clinical symptoms. Minocycline, a second generation tetracycline, has a direct radical scavenging property due to its chemical structure. It has been reported that minocycline is similar to deferoxamine in its ability to chelate iron. Minocycline is also involved in preventing the upregulation of proinflammatory cytokines. The iron-chelating, antioxidant, and anti-inflammatory effects of minocycline were involved in this case.

DOI： 10.1097/MD.0000000000003594

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© 2015 The Authors. Psychiatry and Clinical Neurosciences. Aims Previous studies have supported the claim that psychological stress induces the production of reactive oxygen species. Several authors have suggested that patients with psychiatric disorders show high levels of oxidative stress markers. We examined different oxidative stress markers in patients with chronic schizophrenia. Methods This study included 29 patients with chronic schizophrenia and 30 healthy volunteers. The concentration of urinary biopyrrins and 8-hydroxydeoxyguanosine (8-OHdG), as measured by enzyme-linked immunosorbent assay, were normalized to the urinary concentration of creatinine. Psychiatric symptoms were assessed by the administration of the Brief Psychiatric Rating Scale (BPRS). Results The concentration of biopyrrins in patients with chronic schizophrenia was significantly higher when compared with healthy volunteers. The correlation between biopyrrin level and the duration of illness was highly significant. There were no significant differences in the levels of urinary 8-OHdG between the two groups. In schizophrenic patients, the level of urinary biopyrrins showed correlations with BPRS scores, while the level of urinary 8-OHdG did not show correlations with BPRS. Conclusions Urinary biopyrrins are increased in patients with chronic schizophrenia while urinary 8-OHdG is not increased. These findings suggest that patients with chronic schizophrenia are under the condition of certain oxidative stresses.

DOI： 10.1111/pcn.12319

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DOI： 10.1016/j.schres.2015.07.042

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DOI： 10.1002/gps.4280

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© Springer-Verlag 2014. Background: Treating schizophrenia patients who fail to respond to antipsychotics is a major challenge, and the percentage of treatment-resistant patients is estimated to be 20-25 %. Recent studies indicate that yokukansan (YKS; D2 and 5HT1A partial agonist and 5HT2A and glutamate antagonist) to be safe and useful in treating behavioral and psychological symptoms associated with dementia and other neuropsychiatric conditions. We aimed at evaluating both the efficacy and safety of YKS in patients with treatment-resistant schizophrenia. Methods: This randomized, multicenter, double-blind, placebo-controlled study was conducted between May 2010 and August 2012. One hundred twenty antipsychotic-treated inpatients from 34 psychiatric hospitals in Japan were included. Patients were randomized to adjuvant treatment with YKS 7.5 g/day or placebo. During a 4-week follow-up, psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) with five factors [excitement/hostility (P4, P7, G8, and G14), depression/anxiety (G1, G2, G3, G4, and G6), cognition (P2, N5, N7, G5, G10, G11, G12, G13, and G15], positive (P1, P3, P5, P6, and G9), and negative (N1, N2, N3, N4, N6, G7, and G16]]. Other assessments included, Clinical Global Impression-Severity (CGI-S), Global Assessment of Functioning (GAF), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The primary efficacy outcome was the change in PANSS five-factor scores. The secondary outcomes were changes in the scores of CGI-S. The analysis was made on a modified intention to treat basis with the help of a last observation carried forward method. Results: YKS showed a tendency of superiority to placebo in reducing total all PANSS five-factor scores in treatmentresistant schizophrenia, but the difference was not statistically significant in total, depression/anxiety, cognition, positive, and negative factors. However, compared to the placebo group, the YKS group showed statistically significant improvements in the PANSS excitement/hostility factor scores (p <0.05). No substantial side effects were recorded. Conclusion: The results of the present study indicate YKS to be a potential adjunctive treatment strategy for treatmentresistant schizophrenia, particularly to improve excitement/hostility symptoms.

DOI： 10.1007/s00213-014-3645-8

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© 2015 Bentham Science Publishers. Activated astrocytes, which can also be referred to as reactive astrocytes or astrogliosis, have been identified in affected regions of common neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Activated astrocytes may be beneficial, promoting neuronal survival due to their production of growth factors and neurotrophins. Activated astrocytes can also be detrimental to neighboring neurons in neuroinflammatory processes. Astrocytes exposed to certain inflammatory stimulants in vitro have been shown to release potentially neurotoxic molecules, including inflammatory cytokines, glutamate, nitric oxide and reactive oxygen species. It has recently been shown that adult human astrocytes stimulated with interferon-γ, a common inflammatory cytokine evidently present in neuropathological brains, exert potent neurotoxicity in vitro. This interferon-γ-induced astrocytic neurotoxicity is mediated by the activation of the Janus kinase-signal transducer and activator of transcription (STAT) 3 pathway in the astrocytes, and involves intracellular phosphorylation of STAT3 at tyrosine-705 residue. Therefore, control of STAT3 activation in human astrocytes may be a promising new therapeutic strategy for a broad spectrum of neurodegenerative and neuroinflammatory disorders where activated astrocytes may contribute to the pathology.

DOI： 10.2174/1871527314666150217122305

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© 2015 Tsuyoshi Miyaoka et al. We aimed at evaluating both the efficacy and safety of TJ-54 (Yokukansan) in patients with treatment-resistant schizophrenia. This randomized, multicenter, double-blind, placebo-controlled study was conducted. Methods. One hundred and twenty antipsychotic-treated inpatients were included. Patients were randomized to adjuvant treatment with TJ-54 or placebo. During a 4-week follow-up, psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Results. TJ-54 showed a tendency of being superior to placebo in reduction total, positive, and general PANSS scores in treatment-resistant schizophrenia, but the difference was not statistically significant in both per-protocol set (PPS) and intention-to-treat (ITT). However, in PPS analysis, compared to the placebo group, the TJ-54 group showed statistically significant improvements in the individual PANSS subscale scores for lack of spontaneity and flow of conversation (TJ-54:-0.23 ± 0.08; placebo:-0.03 ± 0.08, P < 0.018), tension (TJ-54:-0.42 ± 0.09; placebo:-0.18 ± 0.09, P < 0.045), and poor impulse control (TJ-54:-0.39 ± 0.10; placebo:-0.07 ± 0.10, P < 0.037). Conclusions. The results of the present study indicate that TJ-54 showed a tendency of being superior to placebo in reduction PANSS scores in treatment-resistant schizophrenia, but the difference was not statistically significant. However, compared to the placebo group, TJ-54 group showed statistically significant improvements in the individual PANSS subscale scores.

DOI： 10.1155/2015/201592

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© 2014 Elsevier B.V. Neuroinflammation contributes to the pathogenesis of neurological disorders. Anti-inflammatory treatments could potentially be used to slow down the progression of these diseases. We studied the anti-neuroinflammatory activity of gold compounds which have been used to treat rheumatoid arthritis. Non-toxic concentrations of auranofin (0.1-1. μM) significantly reduced the cytotoxic secretions by primary human microglia and microglia-like THP-1 promonocytic cells. Auranofin inhibited primed NADPH-oxidase dependent respiratory burst and secretion of tumor necrosis factor (TNF)-α and nitric oxide by monocytic cells. It had a direct neuroprotective effect on SH-SY5Y neuronal cells. Auranofin could have a novel application in the treatment of neurodegenerative diseases.

DOI： 10.1016/j.jneuroim.2014.08.615

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Background In this study, we evaluated the effect on cognitive function of memantine, behavioral and psychological symptoms of dementia, and the care burden, in patients with moderate-to-severe Alzheimer's disease (AD). Furthermore, with near-infrared spectroscopy (NIRS), we examined the association between effect of memantine and brain blood flow. Methods We evaluated the effect of memantine administration from baseline on Clinical Global Impression-Improvement scale, mini mental state examination (MMSE), Clock Drawing Test (CDT), Neuropsychiatric Inventory (NPI), Japanese version of the Zarit Burden Interview (J-ZBI) and NIRS in two groups, donepezil administration memantine combination group (combination group, n = 19) donepezil administration memantine non-administration group (control group, n = 18) were assessed at weeks 0, 4, 12, and 24. Results Significant difference was found between the combination group and the control group in the score variation of Clinical Global Impression-Improvement scale, MMSE, CDT, NPI, and J-ZBI. In the NIRS measurements, trend oxyhemoglobin reduced suppression was observed in some channels centered on the superior frontal gyrus. A significant correlation was observed in the scores of MMSE, CDT, NPI, and J-ZBI. In addition, a significant positive correlation was also observed between the number of words in NIRS and scores of MMSE and CDT. Conclusions In this study, by administering memantine in AD patients that inhibit the reduction of cerebral blood flow in the prefrontal area and improve clinical symptoms overall cognitive function, behavioral and psychological symptoms of dementia, thereby reducing the care burden of caregivers was suggested. Copyright © 2014 John Wiley & Sons, Ltd.

DOI： 10.1002/gps.4074

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Background: Accumulating evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. We previously reported evidence of schizophrenia-like behaviors and microglial activation in Gunn rats. We concluded that the Gunn rat, which exhibits a high concentration of unconjugated bilirubin, may be useful as an animal model of schizophrenia. On the other hand, there have been numerous reports that minocycline is effective in treating schizophrenia. Methods: In the present study, we investigated the effects of minocycline on performance of behavioral tests (prepulse inhibition (PPI) and novel object recognition test (NORT)) after animals received either 40. mg/kg/d of minocycline or vehicle by intraperitoneal (i.p.) injection for 14 consecutive days. Furthermore, we examined the effects of minocycline on microglial activation in the hippocampal dentate gyrus of Gunn rats and Wistar rats. Results: We found that administration of minocycline for 14. days significantly increased the exploratory preference in retention sessions and tended to improve the PPI deficits in Gunn rats. Immunohistochemistry analysis revealed that microglial cells in the minocycline-treated Gunn rat group showed less expression of CD11b compared to vehicle-treated Gunn and Wistar groups. Conclusions: Our findings suggest that minocycline improves recognition memory and attenuates microglial activation in the hippocampal dentate gyrus of Gunn rats. Therefore, minocycline may be a potential therapeutic drug for schizophrenia. © 2013.

DOI： 10.1016/j.pnpbp.2013.12.017

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Background: The properties of Ca2+ signaling mediated by purinergic receptors are intrinsically linked with functional activity of astrocytes. At present little is known concerning Ca2+-dependent purinergic responses in adult human astrocytes. This work has examined effects of purinergic stimulation to alter levels of intracellular Ca2+ in adult human astrocytes. Ca2+-sensitive spectrofluorometry was carried out to determine mobilization of intracellular Ca2+ following adenosine triphosphate (ATP) or 3′-O-(4-benzoyl)benzoyl-ATP (Bz-ATP) stimulation of adult human astrocytes. In some experiments pharmacological modulation of Ca2+ pathways was applied to help elucidate mechanisms of Ca2+ signaling. RT-PCR was also performed to confirm human astrocyte expression of specific purinoceptors which were indicated from imaging studies.Results: The endogenous P2 receptor agonist ATP (at 100 μM or 1 mM) applied in physiological saline solution (PSS) evoked a rapid increase of [Ca2+]i to a peak amplitude with the decay phase of response exhibiting two components. The two phases of decay consisted of an initial rapid component which was followed by a secondary slower component. In the presence of Ca2+-free solution, the secondary phase of decay was absent indicating this prolonged component was due to influx of Ca2+. This prolonged phase of decay was also attenuated with the store-operated channel (SOC) inhibitor gadolinium (at 2 μM) added to standard PSS, suggesting this component was mediated by SOC activation. These results are consistent with ATP activation of P2Y receptor (P2YR) in adult human astrocytes leading to respective rapid [Ca2+]i mobilization from intracellular stores followed by Ca2+ entry through SOC. An agonist for P2X7 receptor (P2X7R), BzATP induced a very different response compared with ATP whereby BzATP (at 300 μM) elicited a slowly rising increase in [Ca2+]i to a plateau level which was sustained in duration. The BzATP-induced increase in [Ca2+]i was not enhanced with lipopolysaccharide pre-treatment of cells as previously found for P2X7R mediated response in human microglia. RT-PCR analysis showed that adult human astrocytes in vitro constitutively express mRNA for P2Y1R, P2Y2R and P2X7R.Conclusion: These results suggest that activation of metabotropic P2YR (P2Y1R and/or P2Y2R) and ionotropic P2X7R could mediate purinergic responses in adult human astrocytes. © 2014 Hashioka et al.; licensee BioMed Central Ltd.

DOI： 10.1186/1471-2202-15-18

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Background: The pathophysiology of schizophrenia (SCZ) remains unclear, and its treatment is far from ideal. We have previously reported that yokukansan (YKS), which is a traditional Japanese medicine, is effective as an adjunctive therapy for SCZ. However, the mechanisms underlying the action of YKS have not yet been completely elucidated. A recent meta-analysis study has shown that adjuvant anti-inflammatory drugs are effective for SCZ treatment, and it has been proposed that some of the cognitive deficits associated with inflammation may in part be related to inflammation-induced reductions in adult hippocampal neurogenesis. Although certain ingredients of YKS have potent anti-inflammatory activity, no study has determined if YKS has anti-inflammatory properties.Methods: Using the Gunn rat, which has been reported as a possible animal model of SCZ, we investigated whether YKS affects cognitive dysfunction in an object-location test and the suppression of microglial activation and neurogenesis in the hippocampus.Results: We found that YKS ameliorated spatial working memory in the Gunn rats. Furthermore, YKS inhibited microglial activation and promoted neurogenesis in the hippocampal dentate gyrus of these rats. These results suggest that the ameliorative effects of YKS on cognitive deficits may be mediated in part by the suppression of the inflammatory activation of microglia.Conclusions: These findings shed light on the possible mechanism underlying the efficacy of YKS in treating SCZ. © 2013 Furuya et al.; licensee BioMed Central Ltd.

DOI： 10.1186/1742-2094-10-145

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Although chromogranin A (CGA) is frequently present in Alzheimer's disease (AD), senile plaques associated with microglial activation, little is known about basic difference between CGA and fibrillar amyloid-β (fAβ) as neuroinflammatory factors. Here we have compared the interleukin-1β (IL-1β) production pathways by CGA and fAβ in microglia. In cultured microglia, production of IL-1β was induced by CGA, but not by fAβ. CGA activated both nuclear factor-κB (NF-κB) and pro-caspase-1, whereas fAβ activated pro-caspase-1 only. For the activation of pro-caspase-1, both CGA and fAβ needed the enzymatic activity of cathepsin B (CatB), but only fAβ required cytosolic leakage of CatB and the NLRP3 inflammasome activation. In contrast, fAβ induced the IL-1β secretion from microglia isolated from the aged mouse brain. In AD brain, highly activated microglia, which showed intense immunoreactivity for CatB and IL-1β, surrounded CGA-positive plaques more frequently than Aβ-positive plaques. These observations indicate differential pathways for the microglial IL-1β production by CGA and fAβ, which may aid in better understanding of the pathological significance of neuroinflammation in AD. © 2013 Elsevier Inc.

DOI： 10.1016/j.neurobiolaging.2013.05.018

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Aims Steroidal and non-steroidal anti-inflammatory drugs are used for treatment of peripheral inflammation, but they are not effective in neurodegenerative disorders. Gold compounds are also used to treat peripheral inflammation, but their effects on neuroimmune reactions are unknown. This study investigated the effects of gold compounds on astrocytic cell functions and assessed in vivo distribution of auranofin after its oral administration in mice. Main methods Auranofin and three other gold compounds were investigated for their ability to reduce the secretion of pro-inflammatory cytokines and cytotoxins produced by activated human astrocytic cells. Ability of the gold compounds to protect neuronal cells from glial cytotoxins and from oxidative damage induced by hydrogen peroxide was also studied. The in vivo distribution of auranofin was investigated using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Key findings Auranofin (0.1-5 μM) inhibited the toxicity of stimulated primary human astrocytes and U-373 MG astrocytic cells towards human neuronal cells, but did not inhibit secretion of cytokines. Treatment of neuronal cells with high nanomolar to low micromolar concentrations of auranofin protected them from toxicity induced by hydrogen peroxide and supernatants of stimulated astrocytic cells through the upregulation of heme-oxygenase (HOX)-1. Aurothiomalate, aurothioglucose, and aurothiosulphate were ineffective in the assays used. Auranofin reached low micromolar concentrations in mouse brains following daily oral administration for one week. Significance Since auranofin may protect neurons by inhibiting astrocyte toxicity and is also directly neuroprotective, it could be useful in neurodegenerative diseases where activation of astrocytes contributes to the neuronal loss. © 2013 Elsevier Inc.

DOI： 10.1016/j.lfs.2013.04.005

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Background: Although schizophrenia affects all age groups, late or very-late-onset schizophrenia-like psychosis has not been well studied, and various treatment issues remain unresolved. The objective of the present study was to evaluate the efficacy and safety of yokukansan (TJ-54), Japanese herbal medicine, monotherapy in a diagnostically homogenous group of elderly patients without cognitive impairment suffering from very-late-onset schizophrenia. Methods: Forty patients of mean age 73.1 ± 4.8 years, fulfilling both the recent consensus criteria for very late-onset schizophrenia-like psychosis and the DSM-IV-TR criteria for schizophrenia, were assessed by the brief psychiatric rating scale, the clinical global impression scale-severity, and positive and negative syndrome scale at baseline and after 4 weeks administration of TJ-54 (2.5-7.5 g/day). In addition, abnormal movements were evaluated with the Simpson-Angus scale, Barnes Akathisia scale, and abnormal involuntary movement scale. Results: A highly significant (p < 0.001) improvement on all measures of psychotic symptomatology was observed in all patients. TJ-54 was very well tolerated by the patients, and no clinically significant adverse effects were observed. Scores on all abnormal movement scales did not differ significantly prior to and after TJ-54 treatment. Conclusion: Preliminary results indicate that TJ-54 appears to be an efficacious and safe herbal medicine for treatment of very-late-onset schizophrenia-like psychosis. © 2013 Elsevier GmbH.

DOI： 10.1016/j.phymed.2013.01.007

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Activated glial cells are capable of generating various inflammatory mediators, including cytokines, nitric oxide and reactive oxygen species. These potentially neurotoxic molecules have been suggested to play a role in the etiology and development of depression. Accumulating evidence indicates that antidepressants have inhibitory effects on inflammatory activation of glial cells and confer neuroprotection under neuropathological conditions. Such efficacy of antide pressants appears to depend on suppressing microglial production of inflammatory substances and up-regulating both astrocytic secretion of neurotrophins and astrocytic glutamine synthase, which converts neurotoxic glutamate into non-toxic glutamine. Therefore, glial cells, both as source and target of inflammatory molecules, may represent a potential promising target involved in the pathophysiology of depression. Moreover, antidepressants have the possibility to be useful treatment, not only for depression, but for a broad spectrum of neuroinflammatory and neurodegenerative disorders where the pathogenesis is associated with glial activation.

DOI： 10.2174/13894501113146660214

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We examined the effects of L-type calcium channel blockers (CCBs) on toxicity exerted by activated human astrocytes and microglia towards SH-SY5Y human neuronal cells. The CCBs nimodipine (NDP) and verapamil (VPM) both significantly suppressed toxic secretions from human astrocytes and astrocytoma U-373 MG cells that were induced by interferon (IFN)-γ. NDP also inhibited neurotoxic secretions of human microglia and monocytic THP-1 cells that were induced by the combination of lipopolysaccharide and IFN-γ. In human astrocytes, both NDP and VPM reduced IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT) 3. They also inhibited the astrocytic production of IFN-γ-inducible T cell α chemoattractant (I-TAC). These results suggest that CCBs attenuate IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. L-type CCBs, especially NDP, might be a useful treatment option for a broad spectrum of neurodegenerative diseases, including Alzheimer disease, where the pathology is believed to be exacerbated by neurotoxic glial activation. © 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuropharm.2012.05.033

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Backgrounds: Increasing evidence shows that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) possesses potent anti-inflammatory and immunomodulatory properties. It is tempting to evaluate the potential of SAHA as a therapeutic agent in various neuroinflammatory and neurodegenerative disorders.Methods: We examined the effects of SAHA on interferon (IFN)-γ-induced neurotoxicity of human astrocytes and on IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT) 3 in human astrocytes. We also studied the effects of SAHA on the astrocytic production of two representative IFN-γ-inducible inflammatory molecules, namely IFN-γ-inducible T cell α chemoattractant (I-TAC) and intercellular adhesion molecule-1 (ICAM-1).Results: SAHA significantly attenuated the toxicity of astrocytes activated by IFN-γ towards SH-SY5Y human neuronal cells. In the IFN-γ-activated astrocytes, SAHA reduced the STAT3 phosphorylation. SAHA also inhibited the IFN-γ-induced astrocytic production of I-TAC, but not ICAM-1. These results indicate that SAHA suppresses IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway.Conclusion: Due to its anti-neurotoxic and anti-inflammatory properties, SAHA appears to have the therapeutic or preventive potential for a wide range of neuroinflammatory disorders associated with activated astrocytes. © 2012 Hashioka et al.; licensee BioMed Central Ltd.

DOI： 10.1186/1742-2094-9-113

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Altered antioxidant status has been implicated in schizophrenia. Microglia, major sources of free radicals such as superoxide (O2-), play crucial roles in various brain pathologies. Recent postmortem and imaging studies have indicated microglial activation in the brain of schizophrenic patients. We previously demonstrated that atypical antipsychotics including aripiprazole significantly inhibited the release of nitric oxide and proinflammatory cytokines from interferon-γ-stimulated microglia in vitro. Antioxidative effects of antipsychotics via modulating microglial superoxide generation have never been reported. Therefore, we herein investigated the effects of antipsychotics on the O2- generation from phorbol-myristate-acetate (PMA)-stimulated rodent microglia by the electron spin resonance (ESR) spectroscopy and also examined the intracellular mechanism by intracellular Ca2+ imaging and immunostaining. Neuronal damage induced by microglial activation was also investigated by the co-culture experiment.Among various antipsychotics, only aripiprazole inhibited the O2- generation from PMA-stimulated microglia. Aripiprazole proved to inhibit the O2- generation through the cascade of protein kinase C (PKC) activation, intracellular Ca2+ regulation and NADPH oxidase activation via cytosolic p47phox translocation to the plasma/phagosomal membranes. Formation of neuritic beading, induced by PMA-stimulated microglia, was attenuated by pretreatment of aripiprazole.D2R antagonism has long been considered as the primary therapeutic action for schizophrenia. Aripiprazole with D2R partial agonism is effective like other antipsychotics with fewer side effects, while aripiprazole's therapeutic mechanism itself remains unclear. Our results imply that aripiprazole may have psychotropic effects by reducing the microglial oxidative reactions and following neuronal reactions, which puts forward a novel therapeutic hypothesis in schizophrenia research. © 2011 Elsevier B.V.

DOI： 10.1016/j.schres.2011.03.019

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Proton pump inhibitors (PPIs) are known to possess anti-inflammatory properties. Inflammatory processes, including astrocytic activation, are implicated in the pathogenesis of different neurodegenerative diseases. Our recent study has indicated that interferon (IFN)-γ-induced astrocytic neurotoxicity is mediated, at least in part, by phosphorylation of signal transducer and activator of transcription (STAT) 3. We therefore studied the effects of PPIs on IFN-γ-induced neurotoxicity and STAT3 activation of human astrocytes. Both lansoprazole (LPZ) and omeprazole (OPZ) significantly attenuated IFN-γ-induced neurotoxicity of human astrocytes and astrocytoma cells. These drugs inhibited IFN-γ-induced phosphorylation of STAT 3, but not STAT1. We found that LPZ significantly reduced secretion of IFN-γ-inducible T cell α chemoattractant from IFN-γ-activated astrocytes. Neither LPZ nor OPZ suppressed expression of intercellular adhesion molecule-1 by IFN-γ-activated astrocytes. These results suggest that PPIs attenuate IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. PPIs that possess antineurotoxic properties may be a useful treatment option for Alzheimer's disease and other neuroinflammatory disorders associated with activated astrocytes. © 2011 Wiley-Liss, Inc.

DOI： 10.1002/glia.21157

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In vitro cultures of various glial cell types are common systems used to model neuroinflammatory processes associated with age-dependent human neurodegenerative diseases. Even though most researchers choose to use neonatal rodent brain tissues as the source of glial cells, there are significant variations in glial cell functions that are species and age dependent. It has been established that human and swine immune systems have a number of similarities, which suggests that cultured porcine microglia and astrocytes may be good surrogates for human glial cell types. Here we describe a method that could be used to prepare more than 90% pure microglia and astrocyte cultures derived from adult porcine tissues. We demonstrate that both microglia and astrocytes derived from adult porcine brains express functional interferon-γ receptors (IFN-γ-R) and CD14. They become toxic towards SH-SY5Y neuroblastoma cells when exposed to proinflammatory mediators. Upon such stimulation with lipopolysaccharide (LPS) and interferon-γ (IFN-γ), adult porcine microglia, but not astrocytes, secrete tumor necrosis factor-α (TNF-α) while both cell types do not secrete detectable levels of nitric oxide (NO). Comparison of our experimental data with previously published studies indicates that adult porcine glial cultures have certain functional characteristics that make them similar to human glial cells. Therefore adult porcine glial cells may be a useful model system for studies of human diseases associated with adulthood and advanced age. Adult porcine tissues are relatively easy to obtain in most countries and could be used as a reliable and inexpensive source of cultured cells. © 2010.

DOI： 10.1016/j.brainresbull.2010.12.011

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Activation of signal transducer and activator of transcription (STAT) 3 is observable in reactive astrocytes under certain neuropathological conditions. Interferon (IFN)-γ is shown to activate STAT3 in cultured rodent astrocytes. Here we investigated the effects of inhibiting STAT3 signaling on IFNγ-activated human astrocytes since we have recently demonstrated that human astrocytes become neurotoxic when stimulated by IFN?. We found that 5'-deoxy-5'-(methylthio)adenosine (MTA) (300μM), S3I-201 (10μM), STAT3 inhibitor VII (3μM) and JAK-inhibitor I (0.3μM) had anti-neurotoxic effects on IFN-γ (50U/ml)-activated astrocytes and U373-MG astrocytoma cells. Another inhibitor, AG490 (30μM) had no significant effect. The active inhibitors also attenuated IFN-γ-induced phosphorylation of Tyr 705-STAT3 and astrocytic expression of intercellular adhesion molecule-1 (ICAM-1). They also decreased astrocytic production of IFN-γ-inducible T cell α chemoattractant (I-TAC). AG490, which did not affect the Tyr 705-STAT3 phosphorylation or ICAM-1 expression, nevertheless reduced the I-TAC secretion. Because these results indicate that pharmacological inhibition of STAT3 signaling correlates with reduced astrocytic neurotoxicity and ICAM-1 expression, but not that of I-TAC secretion, we consider that STAT3 activation mediates, at least in part, the IFN-γ-induced neurotoxicity and ICAM-1 expression by human astrocytes. © 2010 Elsevier Inc.

DOI： 10.1016/j.nbd.2010.09.018

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Pyrazole derivatives are well documented to possess anti-inflammatory activity but their effects on microglial activation are unknown. We determined the efficacy of the novel pyrazole compound 2-MBAPA (R/S-(±)-2- Methylbenzylamino 2-oxo-N-[4-cyano-1-phenyl-1H-pyrazol-5-yl] acetamide) on activated microglia under conditions relevant to inflammation in Alzheimer's disease (AD) brain. The compound at a non-toxic concentration inhibited secretion of tumor necrosis factor (TNF)-α by activated human microglia and attenuated toxicity of conditioned medium from activated human microglia towards human SH-SY5Y neuroblastoma cells in vitro. The 2-MBAPA neuroprotection was further demonstrated in vivo using an animal model of AD. The compound inhibited microgliosis, but not astrogliosis, in amyloid-β peptide (Aβ)1-42-injected rat brain. 2-MBAPA also diminished neuronal loss in the dentate gyrus caused by Aβ1-42 injection. These results indicate that this novel pyrazole compound confers neuroprotection by inhibiting microglial activation. Therefore, further studies with 2-MBAPA and novel analogues based on this lead compound are warranted in an effort to develop new pharmacological agents that may be useful for slowing down progression of AD and other neuroinflammatory disorders associated with activated microglia. © 2011 - IOS Press and the authors. All rights reserved.

DOI： 10.3233/JAD-2011-110698

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Neuroinflammation is traditionally defined as the brain's innate immune response and is also considered to be a glial-cell propagated inflammation. Increasing evidence indicates that neuroinflammation plays an important role in some cases of major depression and also that antidepressants possess anti-neuroinflammatory properties. Inhibition of neuroinflammation may represent a novel mechanism of action of antidepressant treatment. In vivo studies with animal models of neurological conditions have shown that various types of antidepressants exert inhibitory effects on the expression of inflammatory mediators, including cytokines, as well as on both microgliosis and astrogliosis in the inflamed CNS. In vitro studies using pathologically activated rodent microglia or mixed glial cells have demonstrated that various types of antidepressants diminish glial generation of inflammatory molecules. One of the most plausible mechanisms of such anti-neuroinflammatory efficacy of the drugs, as well as their antidepressant actions, seems to involve elevated intracellular cAMP levels. But the exact mechanism has still to be elucidated. © 2011 Bentham Science Publishers Ltd.

DOI： 10.2174/138955711795906888

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DOI： 10.2174/138955711795906914

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Schizophrenia is one of the most severe psychiatric diseases noted for its chronic and often debilitating processes; affecting approximately 1% of the world's population, while its etiology and therapeutic strategies still remain elusive. In the 1950s, the discovery of antipsychotic effects of haloperidol and chlorpromazine shifted the paradigm of schizophrenia. These drugs proved to be antagonists of dopamine D2 receptor (D2R), thus dopamine system dysfunction came to be hypothesized in the pathophysiology of schizophrenia, and D2R antagonism against dopamine neurons has been considered as the primary therapeutic target for schizophrenia. In addition, abnormalities of glutamatergic neurons have been indicated in the pathophysiology of schizophrenia. On the other hand, recent neuroimaging studies have shown that not only dementia but also schizophrenic patients have a significant volume reduction of some specific regions in the brain, which indicates that schizophrenia may involve some neurodegenerative process. Microglia, major sources of various inflammatory cytokines and free radicals such as superoxide and nitric oxide (NO) in the CNS, play a crucial role in a variety of neurodegenerative diseases such as dementia. Recent postmortem and positron emission computed tomography (PET) studies have indicated that activated microglia may be present in schizophrenic patients. Recent in vitro studies have suggested the anti-inflammatory effects of antipsychotics on microglial activation. In this article, we review the anti-inflammatory effects of antipsychotics on microglia, and propose a novel therapeutic hypothesis of schizophrenia from the perspective of microglial modulation. © 2011 Bentham Science Publishers Ltd.

DOI： 10.2174/138955711795906941

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Microglia, which are a major glial component of the central nervous system (CNS), have recently been suggested to mediate neuroinflammation through the release of pro-inflammatory cytokines and nitric oxide (NO). Microglia are also known to play a critical role as resident immunocompetent and phagocytic cells in the CNS. Immunological dysfunction has recently been demonstrated to be associated with the pathophysiology of depression. However, to date there have only been a few studies on the relationship between microglia and depression. We therefore investigated if antidepressants can inhibit microglial activation in vitro. Our results showed that the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline significantly inhibited the generation of NO and tumor necrosis factor (TNF)-α from interferon (IFN)-γ-activated 6-3 microglia. We further investigated the intracellular signaling mechanism underlying NO and TNF-α release from IFN-γ-activated 6-3 microglia. Our results suggest that paroxetine and sertraline may inhibit microglial activation through inhibition of IFN-γ-induced elevation of intracellular Ca2+. Our results suggest that the inhibitory effect of paroxetine and sertraline on microglial activation may not be a prerequisite for antidepressant function, but an additional beneficial effect. © 2010 Elsevier Inc.

DOI： 10.1016/j.pnpbp.2010.07.015

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Although significant effects of interferon-γ (IFN-γ) on glial cells are well documented, information on the expression level and localization of glial IFN-γ receptors (IFN-γ-R) in the human central nervous system (CNS) is sparse. To examine the glial expression of IFN-γ-R in the human CNS, immunohistochemistry and quantitative analyses were performed on Alzheimer disease hippocampus, Parkinson disease substantia nigra, amyotrophic lateral sclerosis spinal cord and corresponding areas from non-neurological cases. Almost all IFN-γ-R-positive (IFN-γ-R+) cells corresponded to GFAP-positive (GFAP+) astrocytes, while none of IFN-γ-R+ cells corresponded to IBA1-positive (IBA1+) microglia or MBP-positive (MBP+) oligodendrocytes in these neurological cases. We observed a similar pattern of glial IFN-γ-R expression in non-neurological cases. Also, we quantitatively analyzed the IFN-γ-R expression by cultured human glial cells using immunocytochemistry and reverse transcription polymerase chain reaction (RT-PCR). In contrast to in vivo results, almost all IFN-γ-R+ cells were IBA1+ in microglial cultures, GFAP+ in astrocytic cultures and MBP+ in oligodendrocytic cultures. Moreover, no significant difference in IFN-γ-R mRNA expression was found for these glial cell types by RT-PCR. These results suggest that the microglial and oligodendrocytic expression levels of IFN-γ-R are much lower than the astrocytic expression levels in the human CNS in vivo, whereas all three types of glial cells constitutively express IFN-γ-R when cultured in vitro. © 2010 Elsevier B.V.

DOI： 10.1016/j.jneuroim.2010.04.023

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Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, NO, and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+]i) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. In this study, we observed that BDNF induced a sustained increase in [Ca2+]i through binding with the truncated tropomyosin-related kinase B receptor, resulting in activation of the PLC pathway and store-operated calcium entry in rodent microglial cells. RT-PCR and immunocytochemical techniques revealed that truncated tropomyosinrelated kinase B-T1 receptors were highly expressed in rodent microglial cells. Sustained activation of store-operated calcium entry occurred after brief BDNF application and contributed to the maintenance of sustained [Ca2+]i elevation. Pretreatment with BDNF significantly suppressed the release of NO from activated microglia. Additionally, pretreatment of BDNF suppressed the IFN-γ-induced increase in [Ca2+]i, along with a rise in basal levels of [Ca2+]i in rodent microglial cells. We show direct evidence that rodent microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses, and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders. Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved.

DOI： 10.4049/jimmunol.0901326

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Astrocytes and microglia become activated in a broad spectrum of inflammatory neurodegenerative diseases. Activated microglia are widely believed to be the principal source of inflammation-induced neuronal degeneration in these disorders. To investigate the neurotoxic potential of human astrocytes, we exposed them and human astrocytic U-373 MG cells to a variety of inflammatory stimulants. We then assessed the effects of their supernatants on human SH-SY5 cells. When astrocytes and U-373 MG cells were stimulated with interferon (IFN)-γ (150 U/ml), their supernatants significantly reduced SH-SY5Y cell viability. Other powerful inflammatory stimulants such as lipopolysaccharide (0.5 μg/ml), tumor necrosis factor-α (10 ng/ml) and interleukin-1β (10 ng/ml), alone or in combination, were without effect. These combinations were also unable to enhance the IFN-γ effect. The induced cytotoxicities were reversed by JAK inhibitor I, a potent and specific inhibitor of JAKs. This result indicates that the neurotoxic effect was proceeding through the IFN-γ receptor (IFNGR)-JAK-STAT intracellular pathway. To establish that the IFNGR is expressed on both cultured astrocytes and U-373 MG cells, we performed RT-PCR on total RNA extracts to identify a specific IFNGR product. We showed the protein product on these cultured cells by immunocytochemistry using an antibody to IFNGR. Finally, using human postmortem material, we showed sharp upregulation of the IFNGR on activated astrocytes in affected areas in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. These findings suggest that activated astrocytes may become neurotoxic when stimulated by IFN-γ and may therefore exacerbate the pathology in a spectrum of neurodegenerative diseases. © 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neurobiolaging.2008.02.019

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To explore whether proton pump inhibitors (PPIs) possess anti-inflammatory effects on microglia, we investigated the effect of lansoprazole (LPZ) and omeprazole (OPZ) on the toxic action towards SH-SY5Y neuroblastoma cells of supernatants from human microglia and THP-1 cells stimulated by lipopolysaccharide combined with interferon-γ. In addition, we studied the effect of LPZ and OPZ on the THP-1 cell production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 using enzyme-linked immunosorbent assays. We found that both PPIs had a protective effect on the toxicity of supernatants and that there was a synergism of this effect with S-ibuprofen (IBP), a typical non-steroidal anti-inflammatory drug (NSAID). A similar protective effect of LPZ was observed with supernatants from stimulated human microglia. We also found that both PPIs significantly reduced the TNF-α secretion from stimulated THP-1 cells in a concentration dependent manner and that there was a trend towards such reduction of IL-6. These results indicate that PPIs possess anti-inflammatory effects and can decrease human microglial and monocytic neurotoxicity. They suggest that PPIs combined with NSAIDs may be effective in the treatment of a broad spectrum of neurodegenerative diseases associated with activated microglia. © 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.expneurol.2009.02.002

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Increasing evidence of pro-inflammatory mediator expression in major depressions indicate that inflammatory changes may play a role. If this is true, the efficacy of antidepressants may be partially attributable to suppression of inflammation. Various types of antidepressants can suppress serum and plasma levels of pro-inflammatory mediators in patients with major depression. Therefore they can inhibit the production of pro-inflammatory mediators by immune cells. These include glial cells, which are the main sources and targets of cytokines in the brain. This review summarizes the evidence showing that antidepressants have an anti-inflammatory potential. The putative mechanisms are also discussed. Because of the anti-inflammatory effects of antidepressants, they might also act as preventives for neurodegenerative dementias including Alzheimer's disease, where the pathogenesis involves chronic inflammation associated with activated microglia. © 2009 Bentham Science Publishers Ltd.

DOI： 10.2174/187152409787601897

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DOI： 10.2217/14796708.4.2.137

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The activation of the inflammatory/immunological response system is suggested to be related to the pathophysiology of schizophrenia. Aripiprazole is a novel atypical antipsychotic, which is a high-affinity dopamine D2 receptor partial agonist. Atypical antipsychotics, all of which have dopamine D2 receptor antagonism, have recently reported to have significantly inhibitory effects on interferon (IFN)-γ-induced microglial activation in vitro. In the present study, we investigated whether or not aripiprazole also has anti-inflammatory effect on IFN-γ-induced microglial activation. Not quinpirole, dopamine D2 full agonist, but aripiprazole significantly inhibited the generation of nitric oxide (NO) and tumor necrosis factor (TNF)-α from IFN-γ-activated microglia and suppressed the IFN-γ-induced elevation of intracellular Ca2+ concentrations ([Ca2+]i) in murine microglial cells. Increased [Ca2+]i has been reported to be required, but by itself not sufficient, for the release of NO and certain cytokines. As a result, we can speculate that aripiprazole may inhibit IFN-γ-induced microglial activation through the suppression of IFN-γ-induced elevation of [Ca2+]i in microglia. Our results demonstrated that not only antipsychotics which have dopamine D2 receptor antagonism but also aripiprazole have anti-inflammatory effects via the inhibition of microglial activation. Antipsychotics may therefore have a potentially useful therapeutic effect on patients with schizophrenia by reducing the microglial inflammatory reactions. © 2008 International Society for Neurochemistry,.

DOI： 10.1111/j.1471-4159.2008.05435.x

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Reactive microglial cells may exacerbate the pathology in some neurodegenerative disorders. Supernatants of stimulated human microglial cells, or their surrogate THP-1 cells, are lethal to cultured human neuroblastoma. SH-SY5Y cells. To explore this neurotoxicity, we examined the spectrum of proteins generated by THP-1 cells using the technique of stable isotope labeling by amino acids in cell culture (SILAC). Unstimulated cells were grown in medium with light L-[12C6] arginine while cells stimulated by lipopolysaccharide (LPS) plus interferon-γ (IFN-γ) were grown in medium with heavy L-[13C6] arginine. Proteins isolated from the media were digested with trypsin, and relative concentrations of generated peptides determined by mass spectrometry. More than 1,500 proteins or putative proteins were identified. Of these, 174 were increased and 189 decreased by more than twofold in the stimulated cell supernatant. We selected one upregulated protein, prolyl endopeptidase (PEP), for further investigation of its potential contribution to neurotoxicity. We first confirmed its upregulation by comparing its enzymatic activity in stimulated and unstimulated cell supernatants. We then evaluated two specific PEP inhibitors, Boc-Asn-Phe-Pro-aldehyde and Z-Pro-Pro-aldehyde-dimethyl acetal, for their potential to reduce toxicity of stimulated THP-1 cell and human microglia supernatants towards SH-SY5Y cells. We found both to be partially protective in a concentration-dependent manner. Inhibition of PEP may be a therapeutic approach to neurodegenerative disorders including Alzheimer and Parkinson diseases. © 2008 Wiley-Liss, Inc.

DOI： 10.1002/glia.20645

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An accumulating body of evidences point to the significance of neuroinflammation and immunogenetics in schizophrenia, characterized by increased serum concentration of several pro-inflammatory cytokines. In the central nervous system (CNS), the microglial cells are the major immunocompetent cells which release pro-inflammatory cytokines, nitric oxide (NO) and reactive oxygen species to mediate the inflammatory process. In the present study, we investigated whether or not atypical antipsychotics, namely perospirone, quetiapine and ziprasidone, would have anti-inflammatory effects on the activated microglia which may potentiate neuroprotection. All three atypical antipsychotics significantly inhibited NO generation from activated microglia while perospirone and quetiapine significantly inhibited the TNF-α release from activated microglia. Antipsychotics, especially perospirone and quetiapine may have an anti-inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia. © 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2007.06.031

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Microglial phagocytosis of amyloid-β (Aβ) deposits is involved in Aβ clearance in vivo. To explore the ability of microglia to phagocytose β, we cultured human microglia or human monocytic THP-1 cells directly on unfixed frontal cortex sections of an Alzheimer disease (AD) case. We found that when these cells were activated by lipopolysaccharide (LPS) plus interferon (IFN)-γ, they developed ameboid morphology and formed clusters around and attaching to amyloid plaques in the tissue. Some cells adhering to these plaques internalized Aβ and some appeared to be degraded. Nevertheless, no significant reduction of the overall Aβ burden was observed. If the cells were not stimulated, they adhered poorly to the sections. We quantified THP-1 cell adhesion to an AD brain section compared with a normal brain section and found it to be significantly increased. If a brain section was rinsed with phosphate buffered saline containing 0.1% Triton X-100, most LPS/IFN-γ-activated THP-1 cells failed to adhere. However, in co-culture with human astrocytes, the number of adherent THP-1 cells was significantly increased. These results suggest that human microglial cells are capable of adhering to and phagocytosing post mortem AD plaque material but activation may be necessary. Astrocytes may further enhance the process. © 2008 - IOS Press and the authors. All rights reserved.

DOI： 10.3233/JAD-2008-14309

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Circumstantial evidence has suggested that activated microglia may be associated with the pathogenesis of depression. Pro-inflammatory cytokines may also be involved. Therefore, we examined the effects of various types of antidepressants, as well as the mood-stabilizer lithium chloride, on interferon-γ (IFN-γ)-induced microglial production of the pro-inflammatory mediators interleukin-6 (IL-6) and nitric oxide (NO). Treatment of the murine microglial 6-3 cells with 100 U/ml of IFN-γ resulted in an eightfold increase in IL-6 and a tenfold increase in NO into the culture medium. Pretreatment with the selective serotonin reuptake inhibitor fluvoxamine, the relatively selective noradrenaline reuptake inhibitor reboxetine, or the non-selective monoaminergic reuptake inhibitor imipramine, significantly inhibited IL-6 and NO production in a dose-dependent manner. These inhibitions were reversed significantly by SQ 22536, a cyclic adenosine monophosphate (cAMP) inhibitor, and, except for reboxetine, by the protein kinase A (PKA) inhibitor Rp-adenosine3′,5′-cyclic monophosphorothioate triethylammonium salt (Rp-3′,5′-cAMPS). Lithium chloride, which is believed to act by inhibiting the calcium-dependent release of noradrenaline, had a different spectrum of action on microglial 6-3 cells. It enhanced IFN-γ-stimulated IL-6 production and inhibited NO production. The inhibitory effect of lithium chloride was not reversed by either SQ 22536 or Rp-3′,5′-cAMPS. These results suggest that antidepressants have inhibitory effects on IFN-γ-activated microglia and these effects are, at least partially, mediated by the cAMP-dependent PKA pathway. On the other hand, the mood stabilizer and anti-manic agent lithium chloride has mixed effects on IFN-γ-induced microglial activation. © 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.expneurol.2007.03.022

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Microglia has recently been regarded to be a mediator of neuroinflammation via the release of proinflammatory cytokines, nitric oxide (NO) and reactive oxygen species (ROS) in the central nervous system (CNS). Microglia has thus been reported to play an important role in the pathology of neurodegenerative disease, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The pathological mechanisms of schizophrenia remain unclear while some recent neuroimaging studies suggest even schizophrenia may be a kind of neurodegenerative disease. Risperidone has been reported to decrease the reduction of MRI volume during the clinical course of schizophrenia. Many recent studies have demonstrated that immunological mechanisms via such as interferon (IFN)-γ and cytokines might be relevant to the pathophysiology of schizophrenia. In the present study, we thus investigated the effects of risperidone on the generation of nitric oxide, inducible NO synthase (iNOS) expression and inflammatory cytokines: interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α by IFN-γ-activated microglia by using Griess assay, Western blotting and ELISA, respectively. In comparison with haloperidol, risperidone significantly inhibited the production of NO and proinflammatory cytokines by activated microglia. The iNOS levels of risperidone-treated cells were much lower than those of the haloperidol-treated cells. Antipsychotics, especially risperidone may have an anti-inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia. © 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2007.01.019

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There is increasing evidence that microglial activation is one of the major pathogenic factors for Alzheimer's disease (AD) and the inhibition of the inflammatory activation of the microglia thus appears to be neuroprotective and a potentially useful treatment for AD. Phospholipids such as phosphatidylserine (PS) and phosphatidylcholine (PC) have been reported to modulate the immune function of phagocytes. In addition, PS has been reported to be a nootropics that can be used as nonprescription memory or cognitive enhancers. We therefore evaluated the effects of liposomes, which comprise both PS and PC (PS/PC liposomes), on the microglial production of tumor necrosis factor-α (TNF-α), nitric oxide (NO), and superoxide ({radical dot}O2-) induced by amyloid β (Aβ) and interferon-γ (IFN-γ). Pretreatment of microglia with PS/PC liposomes considerably inhibited the TNF-α, NO and {radical dot}O2- production induced by Aβ/IFN-γ. These results suggest that PS/PC liposomes have both neuroprotective and antioxidative properties through the inhibition of microglial activation, thus supporting the nootropic and antidementia effect of PS. © 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.freeradbiomed.2006.12.003

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Microglial activation and inflammatory processes have been implicated in the pathogenesis of a number of neurodegenerative disorders. Recently, peroxynitrite (ONOO-), the reaction product of superoxide ({radical dot}O2-) and nitric oxide (NO) both of which can be generated by activated microglia, has been demonstrated to act as a major mediator in the neurotoxicity induced by activated microglia. On the other hand, phospholipids such as phosphatidylserine (PS) and phosphatidylcholine (PC) have been reported to modulate the immune function of phagocytes. We therefore evaluated the effects of liposomes which comprise both PS and PC (PS/PC liposomes) or PC only (PC liposomes) regarding the production of both {radical dot}O2- and NO by lipopolysaccharide (LPS)/phorbol 12-myristate-13-acetate (PMA)-activated microglia using electron spin resonance (ESR) spin trap technique with a DEPMPO and Griess reaction, respectively. Pretreatment with PS/PC liposomes or PC liposomes considerably inhibited the signal intensity of {radical dot}O2- adduct associated with LPS/PMA-activated microglia in a dose-dependent manner. In addition, pretreatment with PS/PC liposomes also significantly reduced LPS/PMA-induced microglial NO production. In contrast, pretreatment with PC liposomes had no effect on the NO production. These results indicate that PS/PC liposomes can inhibit the microglial production of both NO and {radical dot}O2-, and thus presumably prevent a subsequent formation of ONOO-. Therefore, PS/PC liposomes appear to have both neuroprotective and anti-oxidative properties through the inhibition of microglial activation. © 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuint.2006.10.006

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Publishing type：Research paper (scientific journal)  

We herein report a case of Capgras' syndrome observed in interictal psychosis in which the single-photon emission computed tomography (SPECT) findings before and after the appearance of the psychotic symptoms differed. SPECT with 99mTc-hexamethyl propyleneamine oxine (HMPAO) revealed worsening of hypoperfusion in the entire right hemisphere after onset of the psychotic symptoms. The enhanced hypoperfusion demonstrated by SPECT in the present case seems to indicate a right interhemispheric disconnection resulting in the occurrence of Capgras' syndrome. © 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yebeh.2006.04.016

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After engulfment of apoptotic cells through phosphatidylserine (PS)-mediated recognition, microglia secrete prostaglandin E2 (PGE2), a potent anti-inflammatory molecule in the central nervous system. Despite the clinical significance, the mechanism underlying PGE 2 production by phagocytosis of apoptotic cells is poorly understood. In the present study, we used PS liposomes to elucidate the phagocytic pathway for PGE2 production in microglia, because PS liposomes mimic the effects of apoptotic cells on microglia/macrophages. The level of PGE 2 in the culture medium of primary cultured rat microglia was significantly increased by PS liposomes treatment but not by phosphatidylcholine liposomes treatment. The specific ligand for class B scavenger receptor (SR-B), high density lipoprotein, significantly suppressed PS liposome-induced PGE 2 production. PS liposomes were immediately phagocytosed by microglia and sorted to endosomes/lysosomes. Cyclooxygenase (COX)-2 and membrane-bound prostaglandin E synthase-1 (mPGES-1) were induced by treatment with lipopolysaccharide (LPS) but not with PS liposomes. On the other hand, mPGES-2 and cytosolic PGES (cPGES) that are functionally coupled with COX-1 were upregulated after treatment with PS liposomes or LPS. Furthermore, PS liposome-induced PGE2 production was significantly suppressed by indomethacin, a preferential COX-1 inhibitor, but not by NS-398, a selective COX-2 inhibitor. PS liposomes induced activation of p44/p42 extracellular signal-regulated kinase (ERK) but not p38 mitogen-activated protein kinase in SR-BI independent manner. These observations strongly suggest that the up-regulation of terminal PGESs that are preferentially coupled with COX-1, especially mPGES-2, plays the pivotal role in PS liposome-induced PGE 2 production by microglia. Although SR-BI plays an essential role in PS liposome-induced PGE2 production, other PS-recognizing receptors, possibly PS-specific receptor, could also promote PGE2 production by transducing intracellular signals including p44/p42 ERK after PS liposomes treatment. © 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jneuroim.2005.11.008

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DOI： 10.1176/jnp.2006.18.4.557

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Alzheimer's disease (AD) is one type of dementing central nervous amyloidosis characterized by two different types of fibrillar deposits, namely senile plaques and neurofibrillary tangles. Amyloid-β-proteins (Aβ) are the major constituents of senile plaques. The aggregation of soluble Aβ into insoluble amyloid fibrils is believed to be an important step in the pathogenesis of AD and the prevention of this process therefore seems to be a promising strategy for the treatment of AD. Laminin is an important extracellular matrix (ECM) protein which has been reported to accumulate in the senile plaques. It supports such biological activities as cell adhesion, cell proliferation, neurite outgrowth. Recent reports have revealed that laminin inhibits both Aβ fibril formation and Aβ neurotoxicity in vitro. Laminin-related peptides, which have almost the same biological activities as laminin, have also recently been reported to inhibit Aβ fibril formation and/or Aβ neurotoxicity. Finally, Laminin can induce a complete disaggregation of Aβ amyloid fibrils by disassembly into protofibrils and subsequently into an amorphous aggregate. These results thus suggested that laminin or its related peptides may be useful as an effective therapeutic agent for the treatment of AD. © 2005 Bentham Science Publishers Ltd.

DOI： 10.2174/156801505774913017

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DOI： 10.1097/01.jcp.0000177850.23534.69

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There is increasing evidence that microglial activation has pathogenic influence on Alzheimer's disease. According to in vitro studies, microglia activated by amyloid-β (Aβ) peptides have been reported to damage or kill neurons by the release of neurotoxic molecules such as tumor necrosis factor-α (TNF-α), interleukin-1β, nitric oxide or reactive oxygen species. Although the relationship between the aggregational state of Aβ peptides and their neurotoxic activities has been well investigated, little is known about the relationship between the aggregational state of Aβ peptides and their ability to induce microglial activation. In the present study, we thus performed both structural and biochemical studies to clarify the relationship between the aggregational state of Aβ peptides and their ability to activate microglia. Our results have shown that, in the presence of interferon-γ, the Aβ25-35(M35Nle) peptide had almost the same potency of activating microglia and producing TNF-α as the Aβ25-35 peptide on both protein and mRNA levels, in spite of the fact that former peptide represented much less amyloid fibril formation than the latter in a thioflavine-T fluorometric assay. These results suggest that Aβ fibril formation is not necessarily required for microglial activation by the peptides. © 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuint.2005.05.001

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DOI： 10.1097/01.jcp.0000138774.25268.c9

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We herein report a case of new-onset epileptic seizures induced by carbamazepine in an individual with autism spectrum disorders (ASD). We clinicians should bear in mind the possibility that epileptic seizures may possibly be either precipitated or exacerbated by carbamazepine especially in individuals with ASD. © 2004 Elsevier SAS. All rights reserved.

DOI： 10.1016/j.eurpsy.2004.06.001

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In order to examine the possible involvement of μ-calpain in methylmercury (MeHg)-induced neurotoxicity in developing cortical neurons, we performed biochemical and immunohistochemical studies utilizing two antibodies which specifically recognize the 150-kDa μ-calpain-specific α-spectrin breakdown product (SBDP) and the active form of μ-calpain in rats on postnatal day 16. Soluble fractions of the cerebral cortex from control rats exhibited slight immunoreactivity for SBDP. Although the amount of SBDP in the cerebral cortex was only slightly increased the day after the final treatment of MeHg (10 mg/kg) for 3 or 7 consecutive days, there was a prominent accumulation of SBDP 3 days after the final treatment of MeHg for 7 consecutive days. On the other hand, the 76-kDa isoform of μ-calpain gradually increased after chronic treatment of MeHg, but markedly decreased 3 days after the final treatment of MeHg for 7 consecutive days. At this stage, many cortical neurons were densely stained with anti-SBDP antibody. The delayed increase in SBDP corresponded well with the delayed nature of the MeHg-induced neurotoxicity. When MK-801 (0.1 mg/kg), a non-competitive antagonist of N-methyl-D-aspartate (NMDA), was administered intraperitoneally with MeHg for 7 consecutive days, both neuronal damage and accumulation of SBDP were markedly depressed in the cerebral cortex 3 days after the final treatment. Our results indicate that μ-calpain activation and μ-calpain-mediated proteolysis of α-spectrin preceded neuronal damage in the developing cerebral cortex induced by chronic treatment of MeHg. © 2003 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0165-3806(03)00057-9

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We report the case of a presenile woman with Cotard syndrome, in the context of major depression, who showed an improvement in bilateral frontal hypoperfusion in a SPECT study using 99mTc-HMPAO after undergoing successful treatment with antidepressant therapy. We also retrospectively evaluated her clinical course based on the clinical stages. The symptoms of Cotard syndrome have been reported to change dramatically according to the stages. This peculiarity made it difficult for us to rapidly diagnose Cotard syndrome in the context of major depression, and not dementia, and thereby adequately treat the patient in our case. Differences in the reduced blood flow regions and a time lag from psychiatric remission were observed before the improvement in the SPECT findings when comparing our case with a previously reported case of Cotard syndrome. These differences suggest that the mechanism of Cotard syndrome is still not well understood at the present time.

DOI： 10.1097/00002826-200209000-00011

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We investigated whether or not the Amyloid-β-protein (Aβ) itself spontaneously generates free radicals using electron spin resonance (ESR) spectroscopy while also monitoring the aggregational state of Aβ and Aβ-induced cytotoxicity. The present results demonstrated a four-line spectrum in the presence of Aβ25-35 with N-tert-butyl-α-phenylnitrone (PBN) but not in the presence of PBN alone in phosphate-buffered saline (PBS). The fact that the four-line spectrum obtained for the Aβ25-35/PBN in PBS was completely abolished in the presence of the iron-chelating agent Desferal demonstrated the observed four-line spectrum to be iron-dependent. On the other hand, Aβ25-35 with PBN in phosphate buffer (PB) did not produce any definite four-line spectrum. The present results showed the amyloid fibril formation of Aβ25-35 in PBS to be much higher than that of Aβ25-35 in PB. Moreover, Aβ-induced cytotoxicity assays showed Aβ incubated in PBS to be more cytotoxic than that incubated in PB. These results thus demonstrate that Aβ(25-35) - associated free radical generation is strongly influenced by the aggregational state of the peptides. © 2002 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0024-3205(01)01451-5

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In the present study, we investigated whether or not the Aβ peptide itself spontaneously generates free radicals using electron spin resonance (ESR) spectroscopy while also observing the Aβ fibril formation by negative stain electron microscopy. The present results demonstrated a four-line spectrum in the presence of Aβ(1-40) with N-tert-butyl-α-phenylnitrone (PBN) but not in the presence of PBN alone in phosphate-buffered saline. Negative stain electron microscopy has shown that Aβ peptides after 96 h of incubation showed more amyloid-like fibrils than those after 72 h of incubation while the four-line spectrum obtained by ESR spectroscopy attained a maximum intensity after 72 h of incubation and thereafter its intensity immediately decreased during the 4-day incubation period. These results were also supported by a thioflavine-T (Th-T) fluorometric assay. In conclusion, the present results suggest that Aβ-associated free radical generation is correlated with Aβ fibril formation while its generation is only observed transiently during the process of Aβ fibril formation. © 2001 Elsevier Science Ireland Ltd.

DOI： 10.1016/S0304-3940(01)01756-6

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Publishing type：Research paper (scientific journal)  

In the present study, we investigated whether or not the amyloid-β protein (Aβ) peptide itself spontaneously generates free radicals using electron spin resonance (ESR) spectroscopy while also monitoring the aggregational state of Aβ and Aβ-induced cytotoxicity. The present results demonstrated a four-line spectrum in the presence of both Aβ40 and Aβ42 with N-tert-butyl-α-phenylnitrone (PBN), but not in the presence of PBN alone in phosphate-buffered saline (PBS). The fact that the four-line spectrum obtained for the Aβ/PBN in PBS was completely abolished in the presence of the iron-chelating agent Desferal demonstrated the observed four-line spectrum to be iron-dependent. The present study also revealed that either Aβ40 or Aβ42 with PBN in phosphate buffer (PB) did not produce any definite four-line spectrum. Both a thioflavine-T (Th-T) fluorometric assay and circular dichroism (CD) spectroscopy showed the amyloid fibril formation of Aβ in PBS to be much higher than that of Aβ in PB. Moreover, Aβ-induced cytotoxicity assays showed Aβ incubated in PBS to be more cytotoxic than that incubated in PB. These results thus suggest that Aβ-associated free radical generation is strongly influenced by the aggregational state of the peptides.

DOI： 10.1046/j.1471-4159.2001.00392.x

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：English   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：English   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：English   Publisher：SPRINGER HEIDELBERG  

DOI： 10.1007/s00406-015-0610-4

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：English   Publisher：日本脳科学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(株)ワールドプランニング  

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Language：English   Publisher：(一財)聖マリアンナ会聖マリアンナ医学研究所  

自殺率と経済的問題などの生活問題との関係について検討するため、1990〜2009年に東京の百貨店で販売された商品券の額と年間自殺率との関係を調べ、統計的解析を行なった。百貨店で販売された商品券の額と自殺率には負の相関が見られ、相関係数は-0.771であった。商品券の販売額は、自殺率変化の指標になり得ることが示された。商品券の額は、社会の経済状態を反映し、人々の生活に影響することから、商品券の販売額と自殺率との間に相関が見られたと考えられた。

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Language：English   Publisher：Japan Brain Science Society  

Brain-derived neurotrophic factor (BDNF) is expressed at high levels in the hippocampal dentate gyrus (DG), and decreased levels of BDNF have been implicated in the pathophysiology of schizophrenia (SCZ). We have previously reported that yokukansan (YKS), which is a traditional Japanese medicine, is effective for SCZ and promotes neurogenesis in the DG of Gunn rats, an animal model of SCZ. In this study, we investigated the effect of YKS on serum BDNF levels in Gunn rats. The results showed that YKS increased serum BDNF in this model, which may suggest that BDNF expression in the DG leads to increased neurogenesis. Our findings may help to explain the efficacy of YKS in treating SCZ.

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Language：Japanese   Publisher：(株)自然科学社  

不眠を伴う精神疾患に対するラメルテオンの併用投与による(非)ベンゾジアゼピン系睡眠薬の減量効果について検討した。(非)ベンゾジアゼピン系睡眠薬を服用中で、(非)ベンゾジアゼピン系睡眠薬を減量ないし中止する目的で新たにラメルテオンを追加投与し、その後6ヵ月間以上継続投与した66例を対象とした。最終時に66例中24例が(非)ベンゾジアゼピン系睡眠薬を減量ないし中止ができ、そのうち8例が中止できた。(非)ベンゾジアゼピン系睡眠薬の平均ジアゼパム換算値(ジアゼパム5mg錠数換算値)は、減量群では2.54錠相当から0.8錠相当へと、約3分の1の減量が達成でき、有意差を認めた。ラメルテオン減量群および中止群と非減量群における7つの睡眠の評価項目のいずれの項目も、最終時と比較して、すべての項目で有意に改善した。ふらつきや転倒、反跳性不眠などの副作用が問題になって投与を中止した症例は認めなかった。

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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Language：English   Publisher：日本神経化学会  

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