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Title: TRPM2 channel aggravates CNS inflammation and cognitive impairment via activation of microglia in chronic cerebral hypoperfusion.
Authors: Miyanohara, Jun
Kakae, Masashi
Nagayasu, Kazuki
Nakagawa, Takayuki
Mori, Yasuo
Arai, Ken
Shirakawa, Hisashi
Kaneko, Shuji
Author's alias: 宮之原, 遵
抱, 将史
永安, 一樹
中川, 貴之
森, 泰生
荒井, 健
白川, 久志
金子, 周司
Keywords: cerebral hypoperfusion
cognitive impairment
white matter injury
Issue Date: 4-Apr-2018
Publisher: Society for Neuroscience
Journal title: The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume: 38
Issue: 14
Start page: 3520
End page: 3533
Abstract: Chronic cerebral hypoperfusion is a characteristic seen in widespread CNS diseases, including neurodegenerative and mental disorders, and is commonly accompanied by cognitive impairment. Recently, several studies demonstrated that chronic cerebral hypoperfusion can induce the excessive inflammatory responses that precede neuronal dysfunction; however, the precise mechanism of cognitive impairment due to chronic cerebral hypoperfusion remains unknown. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable channel that is abundantly expressed in immune cells and is involved in aggravation of inflammatory responses. Therefore, we investigated the pathophysiological role of TRPM2 in a mouse chronic cerebral hypoperfusion model with bilateral common carotid artery stenosis (BCAS). When male mice were subjected to BCAS, cognitive dysfunction and white matter injury at day 28 were significantly improved in TRPM2-knockout (TRPM2-KO) mice compared with wild-type (WT) mice, whereas hippocampal damage was not observed. There were no differences in blood-brain barrier breakdown and H2O2 production between the two genotypes at 14 and 28 days after BCAS. Cytokine production was significantly suppressed in BCAS-operated TRPM2-KO mice compared with WT mice at day 28. In addition, the number of Iba1-positive cells gradually decreased from day 14. Moreover, daily treatment with minocycline significantly improved cognitive perturbation. Surgical techniques using bone marrow chimeric mice revealed that activated Iba1-positive cells in white matter could be brain-resident microglia, not peripheral macrophages. Together, these findings suggest that microglia contribute to the aggravation of cognitive impairment by chronic cerebral hypoperfusion, and that TRPM2 may be a potential target for chronic cerebral hypoperfusion-related disorders.
Description: 脳の血流低下が認知機能障害を引き起こす --脳の免疫細胞「ミクログリア」による脳内炎症と白質傷害が原因か--. 京都大学プレスリリース. 2018-03-09.
Rights: © 2018 Authors. This paper was deposited under 'AUTHOR LICENSE POLICY'. (
DOI(Published Version): 10.1523/JNEUROSCI.2451-17.2018
PubMed ID: 29507145
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