Elucidation of the mechanism underlying the modulation of microglial function by antidepressants and/or BDNF

阐明抗抑郁药和/或 BDNF 调节小胶质细胞功能的机制

• 批准号: 20790847
• 负责人: MIZOGUCHI Yoshito
• 金额: $ 2.41万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20790847/
• 关键词: 脳由来神経栄養因子(BDNF); ミクログリア; 気分障害; うつ病; カルシウム; 神経炎症; 精神薬理; BDNF; 抗うつ薬; 薬理学; 神経生理学

Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, NO, and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca^<2+> concentration ([Ca^<2+>]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 [Ca^<2+>]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-T1receptors 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 [Ca^<2+>]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 [Ca^<2+>]i, along with a rise in basal levels of [Ca^<2+>]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.

小胶质细胞是内在免疫细胞，其在脑中的干扰后激活后释放因子，包括促炎细胞因子、NO和神经营养因子。细胞内Ca^2+浓度（[Ca^2+]i）的升高对于小胶质细胞的功能（例如从活化的小胶质细胞释放细胞因子和NO）是重要的。越来越多的证据表明，神经精神疾病的病理生理与小胶质细胞介导的炎症反应有关。脑源性神经营养因子（BDNF）是一种神经营养因子，其在小胶质细胞活化以及神经精神疾病的病理生理学和/或治疗中的作用是众所周知的。在这项研究中，我们观察到BDNF通过与截短的原肌球蛋白相关激酶B受体结合，诱导[Ca^<2+>]i的持续增加，导致PLC途径的激活和啮齿动物小胶质细胞中钙库操作的钙内流。RT-PCR和免疫细胞化学技术显示，截短型原肌球蛋白相关激酶B-T1受体在啮齿类小胶质细胞中高度表达。短暂应用BDNF后，钙库操作的钙内流持续激活，并有助于维持持续的[Ca^<2+>]i升高。BDNF预处理可显著抑制激活的小胶质细胞释放NO。此外，BDNF预处理抑制了IFN-γ诱导的啮齿类小胶质细胞[Ca^<2+>]i的增加，沿着[Ca^<2+>]i基础水平的升高。我们的直接证据表明，啮齿类动物的小胶质细胞能够响应BDNF，这可能是重要的炎症反应的调节，也可能参与病理生理和/或治疗神经精神疾病。

项目成果

Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellular Ca2+ regulation in vitro

阿立哌唑通过细胞内 Ca2+ 调节对干扰素 γ 诱导的小胶质细胞活化的体外抑制作用

• 发表时间: 2008
• 期刊: Journal of Neurochemistry 106(2)
• 作者: Kato T;Mizoguchi Y;Monji A;et al
• 通讯作者: et al

Effect of yokukansan on the behavioral and psychological symptoms of dementia in elderly patients with Alzheimer's disease. Prog.

抑肝散对老年阿尔茨海默病痴呆行为和心理症状的影响。

• 发表时间: 2009
• 期刊: Neuropsychopharamacol. Biol. Psychiatry 33
• 作者: Monji A;Takita M;Samejima T;Takaishi T;Hashimoto K;Matsunaga H;Oda M;Sumida Y;Mizoguchi Y;Kato T;Horikawa H;Kanba S
• 通讯作者: Kanba S

Possible role of BDNF-induced microglial intracellular Ca2+ elevation in the pathophysiology of neuropsychiatric disoders.

BDNF 诱导的小胶质细胞内 Ca2+ 升高在神经精神疾病的病理生理学中的可能作用。

• 发表时间: 2009

Brain-derived neurotrophic factor (BDNF) induces sustained elevation of intracellular Ca^<2+> in rodent microglia

脑源性神经营养因子（BDNF）诱导啮齿动物小胶质细胞内Ca^2持续升高

• 发表时间: 2009
• 期刊: Journal of Immunology 183
• 作者: Mizoguchi Y;et al.
• 通讯作者: et al.

Development of Cannabinoid 1 Receptor Protein and Messenger RNA in Monkey Dorsolateral Prefrontal Cortex

• DOI: 10.1093/cercor/bhp179
• 发表时间: 2010-05-01
• 期刊: CEREBRAL CORTEX
• 影响因子: 3.7
• 作者: Eggan, Stephen M.;Mizoguchi, Yoshito;Lewis, David A.
• 通讯作者: Lewis, David A.