TRPM2 Channel Aggravates CNS Inflammation and Cognitive Impairment via Activation of Microglia in Chronic Cerebral Hypoperfusion

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 Ca-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 knock-out (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 HO production between the two genotypes at 14 and 28 d 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. Chronic cerebral hypoperfusion is manifested in a wide variety of CNS diseases, including neurodegenerative and mental disorders that are accompanied by cognitive impairment; however, the underlying mechanisms require clarification. Here, we used a chronic cerebral hypoperfusion mouse model to investigate whether TRPM2, a Ca-permeable cation channel highly expressed in immune cells, plays a destructive role in the development of chronic cerebral hypoperfusion-induced cognitive impairment, and propose a new hypothesis in which TRPM2-mediated activation of microglia, not macrophages, specifically contributes to the pathology through the aggravation of inflammatory responses. These findings shed light on the understanding of the mechanisms of chronic cerebral hypoperfusion-related inflammation, and are expected to provide a novel therapeutic molecule for cognitive impairment in CNS diseases.

TRPM2 channel: A novel target for alleviating ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxic‐ischaemic brain damage

“…Both white matter damage and cognitive dysfunction were prevented by TRPM2-KO. 68 These findings therefore support that the TRPM2 channel also plays a significant role in mediating chronic cerebral hypo-perfusion brain damage. Male mice were used in this study, and it is unclear whether the protection against chronic cerebral hypo-perfusion brain damage by inhibiting the TRPM2 channel is also sex-dependent.…”

“…Kaneko and colleagues have recently examined the role of the TRPM2 channel in mediating chronic cerebral hypo‐perfusion brain damage induced by BCAS in male mice . Significant white matter atrophy and, consistently, impairment in cognitive functions, examined using the Y‐maze test, were observed in mice after they were subjected to hypo‐perfusion for 28 days.…”

“…69 Atrophy BCAS • White matter atrophy in mice was prevented by TRPM2-KO. 68 Cognitive dysfunction MCAO-R • Neurological deficits in mice were significantly attenuated by TRPM2-KO. 63 BCCAO-R • Impairments in learning and memory in mice were suppressed or prevented by TRPM2-KO.…”

“…• Impairments in cognitive function in mice were protected by TRPM2-KO. 68 Sensorimotor dysfunction H-I • Sensorimotor dysfunction was mitigated in mouse puppies by TRPM2-KO. 69 Abbreviations: BCAS, bilateral common carotid artery stenosis; BCCAO-R, bilateral common carotid artery occlusion-reperfusion; CA-R, cardiac arrest-resuscitation; CTZ, clotrimazole; H-I, hypoxia-ischaemia; MCAO-R, middle cerebral artery occlusion-reperfusion; ODG-R, oxygen-glucose deprivation; TRPM2-KO, TRPM2-knockout.…”

Physiological and Pathophysiological Roles of Transient Receptor Potential Channels in Microglia-Related CNS Inflammatory Diseases

“…44) Chronic cerebral hypoperfusion manifests in a wide range of CNS diseases, including neurodegenerative disorders and mental disorders that are accompanied by cognitive impairment; however, the underlying mechanisms remain unclear. In this study, chronic cerebral hypoperfusion can be modeled in mice by bilateral common carotid artery stenosis (BCAS), which results in a decline in cognitive function and excessive release of pro-inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin 6 (IL6), all of which were suppressed in TRPM2 knockout mice.…”