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Schizophrenia is a psychiatric disorder that affects around 1% of the population in widespread populations, with severe cases leading to long-term hospitalization and necessitation of lifelong treatment. Recent studies on schizophrenia have highlighted the involvement of inflammatory and immunoregulatory mechanisms with the onset of symptoms, and the usage of anti-inflammatory treatments are being tested against periods of rapid psychosis. In the central nervous system, microglia are the innate immune population which are activated in response to a wide range of physical and psychological stress factors and produce proinflammatory mediators such as cytokines. Microglial activation and neuroinflammation has been associated to numerous psychiatric disorders including schizophrenia, especially during psychotic episodes. Thus, novel treatments which dampen microglial activation may be of great relevance in the treatment of psychiatric disorders. Fingolimod (FTY720) is a drug used as an immunosuppressive treatment to multiple sclerosis. Recent clinical trials have focused on FTY720 as a treatment for the behavioral symptoms in schizophrenia. However, the mechanisms of Fingolimod in treating the symptoms of schizophrenia are not clear. In this study we use a recently developed neuroinflammatory psychosis model in mice: cuprizone short-term exposure, to investigate the effects of FTY720 administration. FTY720 administration was able to completely alleviate methamphetamine hypersensitivity caused by cuprizone exposure. Moreover, administration of FTY720 improved multiple measures of neuroinflammation (microglial activation, cytokine production, and leucocyte infiltration). In conclusion, our results highlight the future use of FTY720 as a direct anti-inflammatory treatment against microglial activation and psychosis.

DOI： 10.1186/s13041-023-01047-5

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Axonal injury and demyelination occur in demyelinating diseases, such as multiple sclerosis, and the detachment of myelin from axons precedes its degradation. Paranodes are the areas at which each layer of the myelin sheath adheres tightly to axons. The destruction of nodal and paranodal structures during inflammation is an important pathophysiology of various neurological disorders. However, the underlying pathological changes in these structures remain unclear. Kallikrein 6 (KLK6), a serine protease produced by oligodendrocytes, is involved in demyelinating diseases. In the present study, we intraperitoneally injected mice with LPS for several days and examined changes in the localization of KLK6. Transient changes in the intracellular localization of KLK6 to paranodes in the spinal cord were observed during LPS-induced systemic inflammation. However, these changes were not detected in the upper part of brain white matter. LPS-induced changes were suppressed by minocycline, suggesting the involvement of microglia. Moreover, nodal lengths were elongated in LPS-treated wild-type mice, but not in LPS-treated KLK6-KO mice. These results demonstrate the potential involvement of KLK6 in the process of demyelination.

DOI： 10.1007/s11064-023-03929-5

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：Japanese Society for Alternative to Animal Experiments  

Evaluations of the toxicity of hazardous substances in foods and other products are essential. Metals are severely neurotoxic to humans. To date, neurotoxicity has mainly been examined in animal experiments using rodents; however, the importance of using <i>in vitro</i> systems has recently been reported. Although the brain also contains glial cells, <i>in vitro</i> assessments of neurotoxicity have mainly been performed using neurons. Therefore, we established a high-throughput evaluation system by creating a mixed culture system of microglia, a type of glial cell, and neurons using BV2 and Neuro2A cells. The mixed culture showed changes in gene expression compared to the monoculture. Furthermore, in examinations of the toxicities of various metals, some exhibited different toxicities in the mixed culture from those in the single culture. These results suggest that the conventional evaluation system using single cultures is insufficient and also that the use of glial cells to accurately assess neurotoxicity may be necessary.

DOI： 10.11232/aatex.28.8

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DOI： 10.1111/pcn.13505

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/pcn.13505

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DOI： 10.1002/npr2.12298

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The pathophysiology of Alzheimer’s disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-d-aspartate (NMDA) receptors used as an anti-Alzheimer’s drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human β-Amyloid (1–42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1β, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-β and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human β-Amyloid (1–42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of β-Amyloid (1–42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain. 2+ 2+ 2+

DOI： 10.1038/s41598-021-85625-4

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Interpersonal difficulties are often observed in major depressive disorder (MDD), while the underlying psychological and biological mechanisms have not yet been elucidated. In the present case–control study, a PC-based trust game was conducted for 38 drug-free MDD patients and 38 healthy controls (HC). In the trust game, participants invested money in a partner (trusting behaviors), and also rated each partner’s attractiveness (preference for others). In addition, blood biomarkers including metabolites were measured. Both MDD and HC males exhibited more trusting behaviors compared to females. MDD males’ preference for ordinary-attractive partners (lay-person photographs) was lower than HC males, whereas their preference for high-attractive females (fashion-model photographs) was similar levels to HC males. This tendency in MDD males could reflect a “focused (narrowed) preference for females”. As for blood biomarker analysis, the levels of 37 metabolites including acetylcholine, AMP, GMP, nicotinic acid and tryptophan were significantly different between two groups. Interestingly, among male participants, acetylcholine and nicotinic acid were negatively correlated with the level of focused preference for photographed females. In sum, we have revealed some behavioral, psychological and biological traits of trusting behaviors and preference for others especially in MDD males. Larger studies should be conducted to validate our preliminary findings.

DOI： 10.1038/s41598-020-75115-4

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

Targeting the unique glioma immune microenvironment is a promising approach in developing breakthrough immunotherapy treatments. However, recent advances in immunotherapy, including the development of immune checkpoint inhibitors, have not improved the outcomes of patients with glioma. A way of monitoring biological activity of immune cells in neural tissues affected by glioma should be developed to address this lack of sensitivity to immunotherapy. Thus, in this study, we sought to examine the feasibility of non-invasive monitoring of glioma-associated microglia/macrophages (GAM) by utilizing our previously developed induced microglia-like (iMG) cells. Primary microglia (pMG) were isolated from surgically obtained brain tissues of 22 patients with neurological diseases. iMG cells were produced from monocytes extracted from the patients’ peripheral blood. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed a significant correlation of the expression levels of representative markers for M1 and M2 microglia phenotypes between pMG and the corresponding iMG cells in each patient (Spearman’s correlation coefficient = 0.5225, <italic>P &amp;lt;</italic>0.0001). Synchronous upregulation of CD206 expression levels was observed in most patients with glioma (6/9, 66.7%) and almost all patients with glioblastoma (4/5, 80%). Therefore, iMG cells can be used as a minimally invasive tool for monitoring the disease-related immunological state of GAM in various brain diseases, including glioma. CD206 upregulation detected in iMG cells can be used as a surrogate biomarker of glioma.

DOI： 10.3389/fimmu.2021.670131

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Background: The relationship between depression and personality has long been suggested, however, biomarker investigations for depression have mostly overlooked this connection. Methods: We collected personality traits from 100 drug-free patients with major depressive disorders (MDD) and 100 healthy controls based on the Five-Factor Model (FFM) such as Neuroticism (N) and Extraversion (E), and also obtained 63 plasma metabolites profiles by LCMS-based metabolome analysis. Results: Partitional clustering analysis using the NEO-FFI data classified all subjects into three major clusters. Eighty-six subjects belonging to Cluster 1 (C1: less personality-biased group) constituted half of MDD patients and half of healthy controls. C2 constituted 50 subjects mainly MDD patients (N + E ), and C3 constituted 64 subjects mainly healthy subjects (N + E ). Using metabolome information, the machine learning model was optimized to discriminate MDD patients from healthy controls among all subjects and C1, respectively. The performance of the model for all subjects was moderate (AUC = 0. 715), while the performance was extremely improved when limited to C1 (AUC = 0. 907). Tryptophan-pathway plasma metabolites including tryptophan, serotonin and kynurenine were significantly lower in MDD patients especially among C1. We also validated metabolomic findings using a social-defeat mice model of stress-induced depression. Limitations: A case-control study design and sample size is not large. Conclusions: Our results suggest that personality classification enhances blood biomarker analysis for MDD patients and further translational investigations should be conducted to clarify the biological relationship between personality traits, stress and depression. high low low high

DOI： 10.1016/j.jad.2020.09.118

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Reactive microglia are suggested to be involved in neurological disorders, and the mechanisms underlying microglial activity may provide insights into therapeutic strategies for neurological diseases. Microglia produce immunological responses to various stimuli, which include fractalkine (FKN or CX3CL1). CX3CR1, a FKN receptor, is present in microglial cells, and when FKN is applied before lipopolysaccharide (LPS) administration, LPS-induced inflammatory responses are inhibited, suggesting that the activation of the FKN signal is beneficial. Considering the practical administration for treatment, we investigated the influence of FKN on immunoreactive microglia using murine primary microglia and BV-2, a microglial cell line. The administration of LPS leads to nitric oxide (NO) production. NO was reduced when FKN was administered 4 h after LPS administration without a change in inducible nitric oxide synthase expression. In contrast, morphological changes, migratory activity, and proliferation were not altered by delayed FKN treatment. LPS decreases the CX3CR1 mRNA concentration, and the overexpression of CX3CR1 restores the FKN-mediated decrease in NO. CX3CR1 overexpression decreased the NO production that is mediated by LPS even without the application of FKN. ATP and ethanol also reduced CX3CR1 mRNA concentrations. In conclusion, the delayed FKN administration modified the LPS-induced microglial activation. The FKN signals were attenuated by a reduction in CX3CR1 by some inflammatory stimuli, and this modulated the inflammatory response of microglial cells, at least partially.

DOI： 10.1371/journal.pone.0252118

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Microglia are intrinsic immune cells that release factors including pro- and anti-inflammatory cytokines, nitric oxide (NO) and neurotrophins following activation in the brain. Elevation of intracellular Ca concentration ([Ca ]i) is important for microglial functions, such as the release of cytokines or NO from activated microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia. Interestingly, proBDNF, the precursor form of mature BDNF, and mature BDNF elicit opposing neuronal responses in the brain. Mature BDNF induces sustained intracellular Ca elevation through the upregulation of the surface expression of TRPC3 channels in rodent microglial cells. In addition, TRPC3 channels are important for the BDNF-induced suppression of NO production in activated microglia. In this study, we observed that proBDNF and mature BDNF have opposite effects on the relative expression of surface p75 neurotrophin receptor (p75 ) in rodent microglial cells. ProBDNF induces a sustained elevation of [Ca ]i through binding to the p75 , which is possibly mediated by Rac 1 activation and TRPM7 channels in rodent microglial cells. Flow cytometry showed that proBDNF increased the relative surface expression of TRPM7. Although proBDNF did not affect either mRNA expression of pro- and anti-inflammatory cytokines or the phagocytic activity, proBDNF potentiates the generation of NO induced by IFN-γ and TRPM7 channels could be involved in the proBDNF-induced potentiation of IFN-γ-mediated production of NO. We show direct evidence that rodent microglial cells are able to respond to proBDNF, which might be important for the regulation of inflammatory responses in the brain. 2+ 2+ 2+ NTR 2+ NTR

DOI： 10.1002/glia.23996

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Aim: Neurofibromatosis type 1 (NF1) is a multifaceted disease, and frequently comorbid with neurodevelopmental disorders such as autism spectrum disorder (ASD) and learning disorder. Dysfunction of adenylyl cyclase (AC) is one of the candidate pathways in abnormal development of neuronal cells in the brain of NF1 patients, while its dynamic abnormalities have not been observed. Direct conversion technology can generate induced-neuronal (iN) cells directly from human fibroblasts within 2 weeks. Just recently, we have revealed that forskolin, an AC activator, rescues the gene expression pattern of iN cells derived from NF1 patients (NF1-iN cells). In this microreport, we show the dynamic effect of forskolin on NF1-iN cells. Methods: iN cells derived from healthy control (HC-iN cells) and NF1-iN cells were treated with forskolin (final concentration 10 μM), respectively. Morphological changes of iN cells were captured by inverted microscope with CCD camera every 2 minutes for 90 minutes. Results: Prior to forskolin treatment, neuron-like spherical-form cells were observed in HC-iN cells, but most NF1-iN cells were not spherical-form but flatform. Only 20 minutes after forskolin treatment, the morphology of the iN cells were dramatically changed from flatform to spherical form, especially in NF1-iN cells. Conclusion: The present pilot data indicate that forskolin or AC activators may have therapeutic effects on the growth of neuronal cells in NF1 patients. Further translational research should be conducted to validate our pilot findings for future drug development of ASD.

DOI： 10.1002/npr2.12144

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Developmental and epileptic encephalopathy (DEE) represents a group of neurodevelopmental disorders characterized by infantile-onset intractable seizures and unfavorable prognosis of psychomotor development. To date, hundreds of genes have been linked to the onset of DEE. GNAO1 is a DEE-associated gene encoding the alpha-O1 subunit of guanine nucleotide-binding protein (Gα ). Despite the increasing number of reported children with GNAO1 encephalopathy, the molecular mechanisms underlying their neurodevelopmental phenotypes remain elusive. We herein present that co-immunoprecipitation and mass spectrometry analyses identified another DEE-associated protein, SPTAN1, as an interacting partner of Gα . Silencing of endogenous Gnao1 attenuated the neurite outgrowth and calcium-dependent signaling. Inactivation of GNAO1 in human-induced pluripotent stem cells gave rise to anomalous brain organoids that only weakly expressed SPTAN1 and Ankyrin-G. Furthermore, GNAO1-deficient organoids failed to conduct synchronized firing to adjacent neurons. These data indicate that Gα and other DEE-associated proteins organize the cytoskeletal remodeling and functional polarity of neurons in the developing brain. O O O

DOI： 10.1096/fj.202001113R

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In preclinical models, it has been reported that social defeat stress activates microglial cells in the CNS. Translocator protein 18 kDa (TSPO) is a mitochondrial protein expressed on microglia in the CNS that has been proposed to be a useful biomarker for brain injury and inflammation. We hypothesized that a TSPO antagonist, ONO-2952, would inhibit the neuroinflammation induced by microglial hyperactivation and associated depressive-like behaviors. An in vitro analysis showed that ONO-2952 suppressed the release of pro-inflammatory cytokines and mitochondrial reactive oxygen species in cultured microglia stimulated by lipopolysaccharide. In mice submitted to chronic social defeat stress, microglia predominantly expressed TSPO in limbic areas implicated in depressive-like behaviors, including the amygdala, ventral hippocampus and nucleus accumbens, in which an increase in the production of pro-inflammatory cytokines in vivo were associated. Treating animals with ONO-2952 during chronic social defeat stress ameliorated impairments in social avoidance and anxiety-like behaviors and suppressed pro-inflammatory cytokine production, suggesting that ONO-2952 exerted an anti-stress effect in this animal model of depression. Thus, targeting TSPO as a candidate for the development of antidepressants that reduce susceptibility to chronic stress could pave the way toward therapeutic interventions for relapse prophylaxis in depression.

DOI： 10.1016/j.neuropharm.2019.107835

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DOI： 10.1016/j.schres.2019.06.010

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© 2019 Suzuki, Ohgidani, Kuwano, Chrétien, Lorin de la Grandmaison, Onaya, Tominaga, Setoyama, Kang, Mimura, Kanba and Kato. Suicide is one of the most disastrous outcomes for psychiatric disorders. Recent advances in biological psychiatry have suggested a positive relationship between some specific brain abnormalities and specific symptoms in psychiatric disorders whose organic bases were previously completely unknown. Microglia, immune cells in the brain, are regarded to play crucial roles in brain inflammation by releasing inflammatory mediators and are suggested to contribute to various psychiatric disorders such as depression and schizophrenia. Recently, activated microglia have been suggested to be one of the possible contributing cells to suicide and suicidal behaviors via various mechanisms especially including the tryptophan-kynurenine pathway. Animal model research focusing on psychiatric disorders has a long history, however, there are only limited animal models that can properly express psychiatric symptoms. In particular, to our knowledge, animal models of human suicidal behaviors have not been established. Suicide is believed to be limited to humans, therefore human subjects should be the targets of research despite various ethical and technical limitations. From this perspective, we introduce human biological studies focusing on suicide and microglia. We first present neuropathological studies using the human postmortem brain of suicide victims. Second, we show recent findings based on positron emission tomography (PET) imaging and peripheral blood biomarker analysis on living subjects with suicidal ideation and/or suicide-related behaviors especially focusing on the tryptophan-kynurenine pathway. Finally, we propose future perspectives and tasks to clarify the role of microglia in suicide using multi-dimensional analytical methods focusing on human subjects with suicidal ideation, suicide-related behaviors and suicide victims.

DOI： 10.3389/fncel.2019.00031

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DOI： 10.1016/j.jad.2018.07.040

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Background: Early intervention in depression has been critical to prevent its negative impact including suicide. Recent blood biomarker studies for major depressive disorder (MDD) have suggested that tryptophan-kynurenine and lipid related metabolites are involved in the pathophysiology of MDD. However, there have been limited studies investigating these blood biomarkers in first-episode drug-naïve MDD, which are particularly important for early intervention in depression. Methods: As an exploratory pilot case-control study, we examined the above blood biomarkers, and analyzed how these biomarkers are associated with clinical variables in first-episode drug-naïve MDD patients, based on metabolome/lipidome analysis. Results: Plasma tryptophan and kynurenine levels were significantly lower in MDD group (N = 15) compared to healthy controls (HC) group (N = 19), and plasma tryptophan was the significant biomarker to identify MDD group (area under the curve = 0.740). Lower serum high density lipoprotein-cholesterol (HDL-C) was the predictive biomarker for severity of depression in MDD group (R2 = 0.444). Interestingly, depressive symptoms were variously correlated with plasma tryptophan-kynurenine and lipid related metabolites. Moreover, plasma tryptophan-kynurenine metabolites and cholesteryl esters (CEs) were significantly correlated in MDD group, but not in HC group. Limitations: This study had small sample size, and we did not use the multiple test correction. Conclusions: This is the first study to suggest that not only tryptophan-kynurenine metabolites but also HDL-C and CEs are important blood biomarkers for first-episode drug-naïve MDD patients. The present study sheds new light on early intervention in clinical practice in depression, and further clinical studies especially large-scale prospective studies are warranted.

DOI： 10.1016/j.jad.2018.01.014

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Accumlating evidence have suggested that diabetes mellitus links dementia, notably of Alzheimer's disease (AD). However, the underlying mechanism remains unclear. Several studies have shown oxidative stress (OS) to be one of the major factors in the pathogenesis of diabetic complications. Here we show OS involvement in brain damage in a diabetic animal model that is at least partially mediated through an AD-pathology-independent mechanism apart from amyloid-β accumulation. We investigated the contribution of the p66Shc signaling pathway to diabetes-related cognitive decline using p66Shc knockout (-/-) mice. p66Shc (-/-) mice have less OS in the brain and are resistant to diabetes-induced brain damage. Moreover, p66Shc (-/-) diabetic mice show significantly less cognitive dysfunction and decreased levels of OS and the numbers of microglia. This study postulates a p66Shc-mediated inflammatory cascade leading to OS as a causative pathogenic mechanism in diabetes-associated cognitive impairment that is at least partially mediated through an AD-pathology-independent mechanism.

DOI： 10.1038/s41598-018-21426-6

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Hikikomori, a severe form of social withdrawal syndrome, is a growing social issue in Japan and internationally. The pathophysiology of hikikomori has not yet been elucidated and an effective treatment remains to be established. Recently, we revealed that avoidant personality disorder is the most common comorbidity of hikikomori. Thus, we have postulated that avoidant personality is the personality underpinning hikikomori. First, we herein show relationships between avoidant personality traits, blood biomarkers, hikikomori-related psychological features, and behavioural characteristics assessed by a trust game in non-hikikomori volunteers. Avoidant personality traits were negatively associated with high-density lipoprotein cholesterol (HDL-C) and uric acid (UA) in men, and positively associated with fibrin degeneration products (FDP) and high sensitivity C-reactive protein (hsCRP) in women. Next, we recruited actual individuals with hikikomori, and compared avoidant personality traits, blood biomarkers, and psychological features between individuals with hikikomori and age-matched healthy controls. Individuals with hikikomori had higher avoidant personality scores in both sexes, and showed lower serum UA levels in men and lower HDL-C levels in women compared with healthy controls. This is the first report showing possible blood biomarkers for hikikomori, and opens the door to clarify the underlying biological pathophysiology of hikikomori.

DOI： 10.1038/s41598-018-21260-w

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DOI： 10.1007/978-981-10-6580-4_18

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer's disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca2+ signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca2+ mobilization in microglial cells.
Methods: We examined whether pretreatment with donepezil affects the intracellular Ca2+ mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells.
Results: In this study, we observed that pretreatment with donepezil suppressed the TNF alpha-induced sustained intracellular Ca2+ elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNF alpha-induced intracellular Ca2+ elevation through the nicotinic alpha 7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNF alpha-mediated intracellular Ca2+ elevation. Pretreatment with donepezil suppressed the TNF alpha-induced intracellular Ca2+ elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNF alpha treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway.
Conclusions: These suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain.

DOI： 10.1186/s12974-017-1033-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Direct conversion technique to produce induced-neuronal (iN) cells from human fibroblasts within 2 weeks is expected to discover unknown neuronal phenotypes of neuropsychiatric disorders. Here, we present unique gene expression profiles in iN cells from patients with neurofibromatosis type 1 (NF1), a single-gene multifaceted disorder with comparatively high co-occurrence of autism spectrum disorder (ASD). Microarray-based transcriptomic analysis on iN cells from male healthy controls and male NF1 patients (NF1-iN cells) revealed that 149 genes expressions were significantly different (110 upregulated and 39 downregulated). We validated that mRNA of MEX3D (mex-3 RNA binding family member D) was lower in NF1-iN cells by real-time PCR with 12 sex-mixed samples. In NF1-iN cells on day 14, higher expression of FOS mRNA was observed with lower expression of MEX3D mRNA. Interestingly, BCL2 mRNA was higher in NF1-iN cells on day 5 (early-period) but not on day 14. Our data suggest that aberrant molecular signals due to NF1 mutations may disturb gene expressions, a subset of which defines continuum of the neuronal phenotypes of NF1 with ASD. Further translational studies using induced pluripotent stem (iPS) cell-derived neuronal cells are needed to validate our preliminary findings especially confirming meanings of analysis using early-period iN cells.

DOI： 10.1038/s41598-017-14440-7

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Fibromyalgia is a refractory disease characterized by chronic intractable pain and psychological suffering, the cause of which has not yet been elucidated due to its complex pathology. Activation of immune cells in the brain called microglia has attracted attention as a potential underlying pathological mechanism in chronic pain. Until recently, however, technological and ethical considerations have limited the ability to conduct research using human microglia. To overcome this limitation, we have recently developed a technique to create human-induced microglia-like (iMG) cells from human peripheral blood monocytes. In this study, we created the iMG cells from 14 patients with fibromyalgia and 10 healthy individuals, and compared the activation of iMG cells between two groups at the cellular level. The expression of tumor necrosis factor (TNF)-alpha at mRNA and protein levels significantly increased in ATP-stimulated iMG cells from patients with fibromyalgia compared to cells from healthy individuals. Interestingly, there was a moderate correlation between ATP-induced upregulation of TNF-alpha expression and clinical parameters of subjective pain and other mental manifestations of fibromyalgia. These findings suggest that microglia in patients with fibromyalgia are hypersensitive to ATP. TNF-alpha from microglia may be a key factor underlying the complex pathology of fibromyalgia.

DOI： 10.1038/s41598-017-11506-4

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Microglia - immune cells in the brain - have recently been highlighted to understand the pathophysiology of psychiatric disorders such as schizophrenia, depression, and autism. In this review paper, we introduce the microglia hypothesis for psychiatric disorders. In addition, we introduce our novel translational research approach to psychiatric disorders using microglia-like (iMG) cells directly induced from human blood, these iMG cells can be produced from peripheral monocytes within two weeks using two cytokines: granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34).

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Several studies have revealed that neuregulins (NRGs) are involved in brain function and psychiatric disorders. While NRGs have been regarded as neuron- or astrocyte-derived molecules, our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia. Previous studies have indicated that microglia are activated in the brains of individuals with autism spectrum disorder (ASD). Therefore, we investigated microglial NRG mRNA expression in multiple lines of mice considered models of ASD. Intriguingly, microglial NRG expression significantly increased in BTBR and socially-isolated mice, while maternal immune activation (MIA) mice exhibited identical NRG expression to controls. Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain. To translate these findings for application in clinical psychiatry, we measured levels of NRG1 splice-variant expression in clinically available PBMCs of patients with ASD. Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD (as assessed using the Autistic Diagnostic Interview-Revised test: ADI-R). These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD.

DOI： 10.1016/j.bbi.2017.01.003

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The pathophysiology of bipolar disorder, especially the underlying mechanisms of the bipolarity between manic and depressive states, has yet to be clarified. Microglia, immune cells in the brain, play important roles in the process of brain inflammation, and recent positron emission tomography studies have indicated microglial overactivation in the brain of patients with bipolar disorder. We have recently developed a technique to induced microglia-like (iMG) cells from peripheral blood (monocytes). We introduce a novel translational approach focusing on bipolar disorder using this iMG technique. We hypothesize that immunological conditional changes in microglia may contribute to the shift between manic and depressive states, and thus we herein analyzed gene profiling patterns of iMG cells from three patients with rapid cycling bipolar disorder during both manic and depressive states, respectively. We revealed that the gene profiling patterns are different between manic and depressive states. The profiling pattern of case 1 showed that M1 microglia is dominant in the manic state compared to the depressive state. However, the patterns of cases 2 and 3 were not consistent with the pattern of case 1. CD206, a mannose receptor known as a typical M2 marker, was significantly downregulated in the manic state among all three patients. This is the first report to indicate the importance of shifting microglial M1/M2 characteristics, especially the CD206 gene expression pattern between depressive and manic states. Further translational studies are needed to dig up the microglial roles in the underlying biological mechanisms of bipolar disorder.

DOI： 10.3389/fimmu.2016.00676

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Evaluating the severity of depression (SOD), especially suicidal ideation (SI), is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD)-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ)-9. However, these evaluation systems have relied on a person's subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS), and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB), betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA)) are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In addition, modification of these metabolites by diet and/or medications may be a novel therapeutic target for depression. To clarify these aspects, clinical trials measuring metabolites before/after interventions should be conducted. Larger cohort studies including non-clinical subjects are also warranted to clarify our pilot findings.

DOI： 10.1371/journal.pone.0165267

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Viral infections during fetal and adolescent periods, as well as during the course of schizophrenia itself have been linked to the onset and/or relapse of a psychosis. We previously reported that the unique antipsychotic aripiprazole, a partial D2 agonist, inhibits the release of tumor necrosis factor (TNF)-alpha from interferon-gamma-activated rodent microglial cells. Polyinosinic-polycytidylic acid (polyI:C) has recently been used as a standard model of viral infections, and recent in vitro studies have shown that microglia are activated by polyI:C. Aripiprazole has been reported to ameliorate behavioral abnormalities in polyI:C-induced mice.
To clarify the anti-inflammatory properties of aripiprazole, we investigated the effects of aripiprazole on polyI: C-induced microglial activation in a cellular model of murine microglial cells and possible surrogate cells for human microglia.
PolyI:C treatment of murine microglial cells activated the production of TNF-alpha and enhanced the p38 mitogen-activated protein kinase (MAPK) pathway, whereas aripiprazole inhibited these responses. In addition, polyI: C treatment of possible surrogate cells for human microglia markedly increased TNF-alpha mRNA expression in cells from three healthy volunteers. Aripiprazole inhibited this increase in cells from two individuals. PolyI: C consistently increased intracellular Ca2+ concentration ([Ca2+](i)) in murine microglial cells by influx of extracellular Ca2+. We demonstrated that transient receptor potential in melastatin 7 (TRPM7) channels contributed to this polyI: C-induced increase in [Ca2+](i).
Taken together, these data suggest that aripiprazole may be therapeutic for schizophrenia by reducing microglial inflammatory reactions, and TRPM7 may be a novel therapeutic target for schizophrenia. Further studies are needed to validate these findings. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2016.08.022

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The role of microglia in stress responses has recently been highlighted, yet the underlying mechanisms of action remain unresolved. The present study examined disruption in working memory due to acute stress using the water-immersion resistant stress (WIRS) test in mice. Mice were subjected to acute WIRS, and biochemical, immunohistochemical, and behavioral assessments were conducted. Spontaneous alternations (working memory) significantly decreased after exposure to acute WIRS for 2 h. We employed a 3D morphological analysis and site- and microglia-specific gene analysis techniques to detect microglial activity. Morphological changes in hippocampal microglia were not observed after acute stress, even when assessing ramification ratios and cell somata volumes. Interestingly, hippocampal tumor necrosis factor (TNF)-alpha levels were significantly elevated after acute stress, and acute stress-induced TNF-alpha was produced by hippocampal-ramified microglia. Conversely, plasma concentrations of TNF-alpha were not elevated after acute stress. Etanercept (TNF-alpha inhibitor) recovered working memory deficits in accordance with hippocampal TNF-alpha reductions. Overall, results suggest that TNF-a from hippocampal microglia is a key contributor to early-stage stress-to-mental responses. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbi.2015.08.022

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Traditionally, neuroscience had dominantly focused on neurons, however the majority of cells in the brain are not neurons but glial cells including astrocytes, oligodendrocytes and microglia. Historically, the pathophysiology of psychiatric disorders has come to be understood within the neuronal doctrine including the understandings of synaptic connections and neuronal networks. Recent human postmortem and imaging studies have indicated dysfunctions of neuron-glia interaction in various psychiatric disorders such as schizophrenia, depression and autism. We briefly introduce recent topics of glia-related pathophysiology of psychiatric disorders based on rodent and human postmortem and imaging studies. On the other hand, the most significant limitation in psychiatric research is that we cannot obtain living brain cells, including glial cells, from living human subjects based on ethical issues. We herein summarize a novel technique to produce directly induced neuronal and glial cells from somatic cells (not from the brain) such as skin fibroblasts and peripheral bloods by utilizing a gene-modification technique and/or chemical applications. Based on the above-technique, we propose a novel translational study combining with a multi-dimensional perspective; brain imaging analysis, psychometric assessments and molecular functional analysis of induced neuronal and glial cells in psychiatric patients.

DOI： 10.3233/NIB-160109

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS RESEARCH FOUNDATION  

Microglia, glial cells with immunological functions, have been implicated in various neurological diseases and psychiatric disorders in rodent studies, and human postmortem and PET studies. However, the deeper molecular implications of living human microglia have not been clarified. Here, we introduce a novel translational research approach focusing on human microglia. We have recently developed a new technique for creating induced microglia-like (iMG) cells from human peripheral blood. Two cytokines, GM-CSF and IL-34, converted human monocytes into the iMG cells within 14 days, which show various microglial characterizations; expressing markers, forming a ramified morphology, and phagocytic activity with various cytokine releases. We have already confirmed the applicability of this technique by analyzing iMG cells from a patient of Nasu-Hakola disease (NHD; Ohgidani et al., 2014). We herein show possible applications of the iMG cells in translational research. We believe that this iMG technique will open the door to explore various unknown dynamic aspects of human microglia in psychiatric disorders. This also opens new routes for psychopharmacological approach such as drug efficacy screening and personalized medicine.

DOI： 10.3389/fncel.2015.00184

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Microglia are immune cells that release factors, including proinflammatory cytokines, nitric oxide (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 sought to examine the underlying mechanism of BDNF-induced sustained increase in [Ca2+](i) in rodent microglial cells. We observed that canonical transient receptor potential 3 (TRPC3) channels contribute to the maintenance of BDNF-induced sustained intracellular Ca2+ elevation. Immunocytochemical technique and flow cytometry also revealed that BDNF rapidly up-regulated the surface expression of TRPC3 channels in rodent microglial cells. In addition, pretreatment with BDNF suppressed the production of NO induced by tumor necrosis factor alpha (TNF alpha), which was prevented by co-adiministration of a selective TRPC3 inhibitor. These suggest that BDNF induces sustained intracellular Ca2+ elevation through the up-regulation of surface TRPC3 channels and TRPC3 channels could be important for the BDNF-induced suppression of the NO production in activated microglia. We show that TRPC3 channels could also play important roles in microglial functions, which might be important for the regulation of inflammatory responses and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders.

DOI： 10.1074/jbc.M114.555334

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Microglia have been implicated in various neurological and psychiatric disorders in rodent and human postmortem studies. However, the dynamic actions of microglia in the living human brain have not been clarified due to a lack of studies dealing with in situ microglia. Herein, we present a novel technique for developing induced microglia-like (iMG) cells from human peripheral blood cells. An optimized cocktail of cytokines, GM-CSF and IL-34, converted human monocytes into iMG cells within 14 days. The iMG cells have microglial characterizations; expressing markers, forming a ramified morphology, and phagocytic activity with various cytokine releases. To confirm clinical utilities, we developed iMG cells from a patient of Nasu-Hakola disease (NHD), which is suggested to be directly caused by microglial dysfunction, and observed that these cells from NHD express delayed but stronger inflammatory responses compared with those from the healthy control. Altogether, the iMG-technique promises to elucidate unresolved aspects of human microglia in various brain disorders.

DOI： 10.1038/srep04957

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

A block/homo-mixed polyplex micelle, comprising of cationic homo polymer: poly{N'-[N-(2-aminoethyl)-2-aminoethyl] aspartamide} P[Asp(DET)] and block copolymer: polyethylene glycol (PEG)-b-P[Asp(DET)], has been reported to exhibit the efficient transgene expression in vivo by intratracheal and systemic administration. In the present study, we investigated the potential of immunogene therapy by intraperitoneal (i.p.) administration of block/homopolyplex micelles for peritoneal dissemination. For evaluation of transgene expression in vivo, block/homo polyplex micelles showed 12-fold higher level in luciferase expression evaluated by bioluminescence imaging system at 24 h after the i.p. administration compared with block polyplex micelles composed with only PEG-b-P[Asp(DET)] in nude mice bearing peritoneal dissemination. The distribution of block/homo polyplex micelles and intracellular uptake of pDNA was observed in tumor nodules. The tumor growth and the prolonged survival rate for the mice harboring disseminated pancreatic cancer more significantly compared with the mock. The antitumor effect of GM-CSF gene therapy was mediated via the activation of natural killer cells. For safety evaluation, block/homo polyplex micelles indicated almost no adverse events for patho-physical findings and blood examinations in mice and cynomolgus monkeys, although slight increases in serum fibrinogen were observed in the monkey model. In conclusion, block/homo polyplex micelle-based immunogene therapy via i. p. administration may be a safe and effective approach for suppressing intractable peritoneal dissemination. (C) 2013 Elsevier B. V. All rights reserved.

DOI： 10.1016/j.jconrel.2013.02.006

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC BIOSCIENCE BIOENGINEERING JAPAN  

Shochu distillation remnants (SDR) are by-products in the manufacturing process of the Japanese liquor Shochu and include various useful organic compounds derived from the fermentation of grains. We have obtained valuable powder (PSDR) from freeze-dried SDR by the treatment with ethanol. In this study, we examined the anticancer effects of barley-, rice-, and sweet potato-PSDR against HepG2 and HuH-7 cells of human hepatocellular carcinoma (HCC) in vitro. All PSDR inhibited the growth of both these HCC cells through the induction of apoptosis. Especially, barley-PSDR was the most effective for the growth inhibition and apoptosis induction of HCC cells of all NOR. We next examined the apoptotic mechanisms induced by barley-PSDR Decrease in mitochondrial membrane potential and release of cytochrome c from mitochondria were observed in HCC cells after the treatment with barley-PSDR Furthermore, barley-PSDR induced the nuclear translocation of apoptosis-inducing factor (AlF) from mitochondria, while it did not significantly affect the activities of caspase-3, -8, and -9. The results suggested that barley-NOR induced apoptosis against HCC cells via the caspase-independent mitochondrial pathway. The findings in this study suggest that PSDR has the possibility of therapeutic and/or preventive agents of HCC. (C) 2012, The Society for Biotechnology, Japan. All rights reserved.

DOI： 10.1016/j.jbiosc.2012.02.026

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Shochu distillation remnants (SDR) are by-products in the manufacturing process of the Japanese liquor Shochu and include various useful organic compounds derived from the fermentation of grains. In this study, we investigated the inhibitory effects of barley-, black rice-, rice-, and sweet potato-powder from Shochu distillation remnants (PSDR) on the melanogenesis of B16 cells. Barley- and black rice-PSDR showed significant decrease in the intracellular melanin content and tyrosinase activity without cytotoxicity in the concentration range of 500-1000 mu g/mL. Significantly, the antioxidative capacity of PSDR correlated well with the antimelanogenesis on the basis of a radical-scavenging assay. Furthermore, some antioxidant polyphenols in PSDR were identified by HPLC and the amount of the polyphenols was in good agreement with the antimelanogenic effects of PSDR. These results indicated that the polyphenols are the active components of PSDR for the antimelanogenesis of B16 cells. This study suggests that barley- and black rice-PSDR could be novel antimelanogenic materials for skin whitening. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.foodchem.2011.12.049

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

Barely-Shochu is a traditional Japanese liquor distilled from fermented barley with Saccharomyces cerevisiae. Barely-Shochu distillation remnants (SDR) are by-products in the manufacturing process of barley-Shochu. We have already reported on valuable powder from Shochu distillation remnants (PSDR) including antioxidative compounds such as polyphenols. In this study, we investigated the therapeutic effects of barely-PSDR against orthotopic xenograft mouse models of hepatocellular carcinoma (HCC) in vivo. We constructed a mouse model of HCC by orthotopical inoculation of HepG2 cells into the liver of SCID mice. Barely-PSDR (2250 mg/kg) was orally treated once each day for 21 d after the inoculation of HepG2 cells. The livers were removed from anaesthetized mice after the treatment with barely-PSDR and fixed in formalin. The liver sections were analyzed by hematoxylin and eosin (HE) staining and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) methods. Remarkably high reduction of tumorigenesis was obtained in the mouse models of HCC after the oral administration of barely-PSDR in vivo. Induction of apoptosis in the liver section on the mouse models treated with barely-PSDR was observed. Furthermore, prolonged survival was obtained. Thus, therapeutic effects of barely-PSDR without side effects on the orthotopic xenograft mouse models were revealed for the first time.

DOI： 10.1248/bpb.35.984

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Language：Japanese   Publisher：(一社)日本ペインクリニック学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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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：(一社)日本ペインクリニック学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

筆者らは、ヒト血液単球から2週間でミクログリア様(iMG)細胞を作製する技術を開発し、様々な精神神経患者由来のiMG細胞の作製・解析を進めている。本稿では、早発性認知症・双極性障害・線維筋痛症をもつ患者から作製したiMG細胞によるリバーストランスレーショナル研究の知見を紹介する。iMG細胞は、さまざまな脳疾患研究におけるミクログリアの病態解明ツールとして、さらには、脳内ミクログリア動態を反映する客観的バイオマーカーとしての活用が期待される。(著者抄録)

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Language：Japanese   Publisher：日本生物学的精神医学会  

近年,さまざまな精神疾患において脳内炎症,特に,脳内免疫細胞ミクログリア活性化がその病態生理に重要である可能性が示唆されている。筆者らは十年来ミクログリア活性化異常に着目した精神疾患の病態治療仮説を提唱してきた。ヒトでミクログリアの活動性を探る代表的な方法として死後脳の解析やPETを用いた生体イメージング技術が用いられている。しかしながら,こうした脳をみるというダイレクトな方法だけではミクログリアのダイナックで多様な分子細胞レベルの活動を十分に捉えることは困難である。筆者らは,採取しやすい患者の血液を用いて間接的にミクログリア活性化を分子細胞レベルで評価するためのリバース・トンラスレーショナル研究を推進してきた。例えば,ヒト血液単球から2週間でミクログリア様(iMG)細胞を作製する技術を開発し,幾つかの精神疾患患者由来のiMG細胞の解析を進めている。本学会誌では,すでにこうした研究による成果を幾度も報告しており,本稿では,筆者らが最近報告したうつ病患者のメタボローム解析の知見を後半に紹介する。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J05574&link_issn=&doc_id=20210402380004&doc_link_id=%2Fcy8jbiop%2F2021%2F003201%2F005%2F0018-0025%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcy8jbiop%2F2021%2F003201%2F005%2F0018-0025%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：日本生物学的精神医学会  

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Language：Japanese   Publisher：日本生物学的精神医学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J05574&link_issn=&doc_id=20210112320006&doc_link_id=%2Fcy8jbiop%2F2020%2F003104%2F007%2F0186-0186%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcy8jbiop%2F2020%2F003104%2F007%2F0186-0186%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese  

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Language：Japanese   Publisher：日本ストレス学会  

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J02615&link_issn=&doc_id=20200526440046&doc_link_id=%2Fcq3neuro%2F2019%2F003604%2F050%2F0508-0508%26dl%3D2&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcq3neuro%2F2019%2F003604%2F050%2F0508-0508%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

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

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Language：Japanese   Publisher：(公社)日本薬学会  

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Language：Japanese   Publisher：日本生物学的精神医学会  

近年、うつ病をはじめとする気分障害において脳内炎症、特に、脳内免疫細胞ミクログリア活性化がその病態生理に重要である可能性が示唆されており、筆者らは10年来ミクログリア活性化異常に着目した気分障害の病態治療仮説を提唱してきた。ヒトでミクログリアの活動性を探る代表的な方法として死後脳の解析やPETを用いた生体イメージング技術が用いられているが、こうした方法だけではミクログリアのダイナックで多様な活動性を十分に捉えているとは言い難いのが現状である。筆者らは、間接的にミクログリア活性化を評価するための血液バイオマーカー研究を推進してきた。一つは、ヒト末梢血単球にGM-CSFとIL-34を添加することで2週間で作製できる直接誘導ミクログリア様(iMG)細胞を用いた精神疾患モデル細胞研究であり、もう一つは、血漿・血清を用いたメタボローム解析・リピドーム解析などの網羅的解析研究である。本稿では、こうしたヒト血液を用いてのミクログリアに焦点を当てた橋渡し研究を紹介する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J05574&link_issn=&doc_id=20190130410009&doc_link_id=%2Fcy8jbiop%2F2018%2F002904%2F010%2F0182-0188%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcy8jbiop%2F2018%2F002904%2F010%2F0182-0188%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)日本臨床社  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01205&link_issn=&doc_id=20181031150006&doc_link_id=%2Fag6niria%2F2018%2F007611%2F006%2F1937-1942%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2018%2F007611%2F006%2F1937-1942%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J02615&link_issn=&doc_id=20190205230078&doc_link_id=%2Fcq3neuro%2F2018%2F003506%2F082%2F5168-5168%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcq3neuro%2F2018%2F003506%2F082%2F5168-5168%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

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Language：Japanese   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：(株)医学書院  

近年,さまざまな精神疾患において脳内炎症,特に,脳内免疫細胞ミクログリアの過剰活性化が示唆されている。今回の総説では,脳内炎症に重要な働きを担っているミクログリア細胞の活性化異常に着目した精神疾患の病態治療仮説を概説した。さらに,仮説解明のために筆者らが取り組んでいるトランスレーショナルリサーチ(橋渡し研究),特に末梢血単球にGM-CSFとIL34を添加することで2週間以内に作製できる直接誘導ミクログリア様細胞を用いた精神疾患モデル細胞研究を紹介した。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J04871&link_issn=&doc_id=20170927330006&doc_link_id=40021326006&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F40021326006&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Language：Japanese   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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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)ニュー・サイエンス社  

疼痛の病態機序はいまだ十分には解明されていないが、神経障害性疼痛モデル齧歯類等を用いた基礎研究により、脊髄ミクログリアの過剰活性化が示唆されている。つい最近のTSPOリガンドを用いたヒトPET研究では、慢性腰痛患者の脳内において、ミクログリア過剰活性化を示唆する報告がなされたばかりである。こうした知見により、疼痛患者におけるミクログリア過剰活性化仮説はますます注目されるようになった。仮説解明のためには、疼痛患者のミクログリア細胞の活動性をより詳細に解析する必要があるが、患者の脊髄や脳内のミクログリア細胞を直接的にモレキュラーレベルで解析することは技術的に至極困難であり、倫理的にもなされるべきではない。最近、筆者らは、ミクログリアをターゲットとした臨床研究の限界を補うべく、ヒト末梢血単球からわずか2週間でミクログリア様細胞(induced microglia-like cells:以下、iMG細胞)を作製する技術開発に成功した(Ohgidani、Kato et al.Sci Rep 2014)。本稿では、疼痛患者におけるミクログリア過剰活性化仮説解明のために推進しているヒトiMG細胞を用いた橋渡し(トランスレーショナル)研究の一端を紹介する。(著者抄録)

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Language：Japanese   Publisher：(一社)日本神経精神薬理学会  

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Language：Japanese   Publisher：(一社)日本神経精神薬理学会  

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Language：English   Publisher：(一社)日本神経精神薬理学会  

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Language：English   Publisher：(一社)日本神経精神薬理学会  

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Language：Japanese   Publisher：(株)先端医学社  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J03591&link_issn=&doc_id=20160729440008&doc_link_id=%2Fae6mopsb%2F2016%2F001603%2F010%2F0192-0194%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae6mopsb%2F2016%2F001603%2F010%2F0192-0194%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

Web of Science

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Language：Japanese   Publisher：(公財)先進医薬研究振興財団  

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Language：Japanese   Publisher：日本生物学的精神医学会  

脳内の主要な免疫細胞であるミクログリアは、さまざまな脳内環境変化に応答して活動性が高まると、炎症性サイトカインやフリーラジカルといった神経傷害因子を産生し、脳内の炎症免疫機構を司っている。ストレスがミクログリアの活動性を変容させるという知見も齧歯類モデルにより明らかになりつつある。近年の死後脳研究やPETを用いた生体脳研究において、さまざまな精神疾患患者の脳内でミクログリアの過剰活性化が報告されている。精神疾患の病態機構にストレスの寄与は大きく、ストレス→ミクログリア活性化→精神病理(こころの病)というパスウェイが想定されるがほとんど解明されていない。筆者らの研究室では、心理社会的ストレスがミクログリア活動性を介してヒトの心理社会的行動を変容させるという仮説(こころのミクログリア仮説)を提唱し、その解明に向けて、動物とヒトとの知見を繋ぐための双方向性の研究を推進している。健常成人男性においてミクログリア活性化抑制作用を有する抗生物質ミノサイクリン内服により、強いストレス下で性格(特に協調性)にもとづく意思決定が変容することを以前報告しており、最近筆者らが行った急性ストレスモデルマウス実験では、海馬ミクログリア由来TNF-α産生を伴うワーキングメモリー障害がTNF-α阻害薬により軽減させることを見出した。本稿では、こうしたトランスレーショナル研究の一端を紹介する。(著者抄録)

DOI： 10.11249/jsbpjjpp.27.1_2

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J05574&link_issn=&doc_id=20160422580001&doc_link_id=%2Fcy8jbiop%2F2016%2F002701%2F002%2F0002-0007%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcy8jbiop%2F2016%2F002701%2F002%2F0002-0007%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：IOS Press  

Traditionally, neuroscience had dominantly focused on neurons, however the majority of cells in the brain are not neurons but glial cells including astrocytes, oligodendrocytes and microglia. Historically, the pathophysiology of psychiatric disorders has come to be understood within the neuronal doctrine including the understandings of synaptic connections and neuronal networks. Recent human postmortem and imaging studies have indicated dysfunctions of neuron-glia interaction in various psychiatric disorders such as schizophrenia, depression and autism. We briefly introduce recent topics of glia-related pathophysiology of psychiatric disorders based on rodent and human postmortem and imaging studies. On the other hand, the most significant limitation in psychiatric research is that we cannot obtain living brain cells, including glial cells, from living human subjects based on ethical issues. We herein summarize a novel technique to produce directly induced neuronal and glial cells from somatic cells (not from the brain) such as skin fibroblasts and peripheral bloods by utilizing a gene-modification technique and/or chemical applications. Based on the above-technique, we propose a novel translational study combining with a multi-dimensional perspective
brain imaging analysis, psychometric assessments and molecular functional analysis of induced neuronal and glial cells in psychiatric patients.

DOI： 10.3233/NIB-160109

Scopus

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Language：Japanese   Publisher：(公財)金原一郎記念医学医療振興財団  

DOI： 10.11477/mf.2425200355

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00731&link_issn=&doc_id=20151211110014&doc_link_id=10.11477%2Fmf.2425200355&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.2425200355&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：日本生物学的精神医学会  

死後脳研究やPETを用いた生体脳研究により、統合失調症患者、自閉症患者、うつ病患者において脳内免疫細胞ミクログリアの過剰活性化が次々と報告されている。他方で、ミクログリア活性化抑制作用を有する抗生物質ミノサイクリンに抗精神病作用や抗うつ作用が報告されており、筆者らは既存の抗精神病薬や抗うつ薬が齧歯類ミクログリア細胞の活性化を抑制することを報告してきた。筆者らはこうした知見を元に、精神疾患におけるミクログリア仮説を提唱している。本稿では、精神疾患におけるミクログリア仮説解明のために現在進行中のトランスレーショナル研究を紹介する。筆者らの研究室では、安全性の確立されている抗生物質ミノサイクリン投薬によってミクログリアの活動性そのものが精神に与える影響を間接的に探るというトランスレーショナル研究を萌芽的に進めており、健常成人男性の社会的意思決定がミクログリアにより制御される可能性を報告してきた(Watabe,Kato,et al,2013他)。精神疾患に着目したモレキュラーレベルのミクログリア研究では、技術的倫理的側面から生きたヒトの脳内ミクログリア細胞を直接採取して解析することは至極困難であり、モデル動物由来のミクログリア細胞の解析に頼らざるを得ない状況にあった。筆者らは、最近、ヒト末梢血からわずか2週間でミクログリア様細胞(induced microglia-like cells:iMG細胞)を作製する技術を開発した(Ohgidani,Kato,et al,2014)。精神疾患患者由来iMG細胞の作製により、これまで困難であった患者のミクログリア細胞のモレキュラーレベルでの活性化特性が予測可能となった。こうした技術によって、臨床所見(診断・各種検査スコア・重症度など)との相関を解析することで、近い将来、様々な精神病理現象とミクログリア活性化との相関を探ることが可能になるかもしれない。(著者抄録)

DOI： 10.11249/jsbpjjpp.26.3_140

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J05574&link_issn=&doc_id=20151109390003&doc_link_id=%2Fcy8jbiop%2F2015%2F002603%2F004%2F0140-0145%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcy8jbiop%2F2015%2F002603%2F004%2F0140-0145%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：日本ストレス学会  

脳内の主要な免疫細胞であるミクログリアは,さまざまな脳内環境変化に応答して活動性が高まると,炎症性サイトカインやフリーラジカルといった神経傷害因子および神経栄養因子を産生し,脳内の炎症免疫機構を司っていることが齧歯類モデルを用いた研究により明らかになっている。ストレスがミクログリアの活動性を変容させるという知見も齧歯類モデルにより明らかになりつつある。ヒトの精神活動に関しても,近年の死後脳研究やpositron emission tomography(PET)を用いた生体脳研究において,統合失調症患者,自閉症患者,あるいは,慢性疲労症候群患者の脳内でミクログリアの過剰活性化が報告されている。精神疾患の病態機構にストレスの寄与は大きく,ストレス→ミクログリア活性化→精神病理というパスウェイが想定されるがほとんど解明されていない。齧歯類モデル研究には限界があり,筆者の研究室では,ヒトを対象としたミクログリア研究を萠芽的に始動している。1つは,ミクログリア活性化抑制作用を有する抗生物質ミノサイクリン内服による精神活動への影響を計るという介入研究である。他方,筆者らは最近,ヒト末梢血採血により2週間で作製できる単球由来直接誘導ミクログリア様細胞(iMG細胞)を開発し,新しいトランスレーショナル研究技術として導入している。本稿では,ストレスとミクログリアに関する齧歯類モデルの知見を紹介するとともに,ストレス応答を含む精神活動におけるミクログリア活性化仮説を解明するために筆者らが推進しているヒトを対象としたトランスレーショナル研究の一端を紹介する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J02753&link_issn=&doc_id=20150910110007&doc_link_id=%2Ffd6stres%2F2015%2F002904%2F007%2F0373-0388%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Ffd6stres%2F2015%2F002904%2F007%2F0373-0388%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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：(公財)先進医薬研究振興財団  

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Language：English   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：日本ストレス学会  

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

DOI： 10.1016/j.jneuroim.2014.08.320

Web of Science

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Language：Japanese   Publisher：(株)先端医学社  

統合失調症では、1950年代ハロペリドール・クロルプロマジンに抗精神病作用が偶然にも発見され、これらの薬剤が神経ドパミンD2受容体拮抗作用を有することから、ドパミン仮説が提唱されて久しい。しかし、統合失調症の病態治療機序は依然解明されていない。炎症性サイトカインやフリーラジカルなど末梢バイオマーカーの異常が統合失調症患者で指摘されており、最近では、統合失調症患者で脳内免疫細胞ミクログリアの活性化が報告されている。筆者らは、in vitro実験によって、神経・シナプス系にばかり作用すると信じられてきた抗精神病薬が、げっ歯類ミクログリア細胞へ直接的に作用し、フリーラジカルや炎症性サイトカインの産生抑制を介して、脳保護的に作用する可能性を報告してきた。これらを手がかりに、現在筆者らが検証を進めているミクログリア活性化とその制御を介した統合失調症の慢性炎症仮説を紹介する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J03591&link_issn=&doc_id=20140121520003&doc_link_id=%2Fae6mopsb%2F2014%2F001401%2F004%2F0015-0022%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae6mopsb%2F2014%2F001401%2F004%2F0015-0022%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器外科学会  

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Language：Japanese   Publisher：日本臨床分子医学会  

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Language：English   Publisher：(一社)日本癌学会  

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