TRPM2 channel aggravates CNS inflammation and cognitive impairment via activation of microglia in chronic cerebral hypoperfusion.

DOI HANDLE Web Site 9 Citations 69 References Open Access
  • Miyanohara, Jun
    Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Kakae, Masashi
    Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Nagayasu, Kazuki
    Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Nakagawa, Takayuki
    Department of Clinical Pharmacology and Therapeutics, Kyoto University
  • Mori, Yasuo
    Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University
  • Arai, Ken
    Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School
  • Shirakawa, Hisashi
    Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Kaneko, Shuji
    Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University

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.

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