TRPA1 plays a protective role in cognitive impairment and white matter injury in chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion (CCH), resulting in an inadequate supply of blood to the brain, is manifested in various CNS diseases including neurodegenerative and mental disorders that are accompanied by cognitive impairment and associated with oxidative stress. Transient receptor potential ankyrin 1 (TRPA1), an oxidative stress-sensitive Ca2+-permeable non-selective cation channel, is recently found to be expressed in brain cells, although the role of TRPA1 in the CNS diseases is controversial. In this study, we investigated the pathophysiological role of TRPA1 in CCH using a mouse bilateral common carotid artery stenosis (BCAS) with 0.18 mm-diameter microcoils. At 28 days after operation, BCAS-operated mice showed cognitive impairment and white matter injury in wild-type (WT) and TRPA1-knockout (TRPA1-KO) mice. On the other hand, at 14 days after operation, BCAS-operated TRPA1-KO mice showed cognitive impairment and white matter injury, whereas these dysfunctions were not observed in WT mice. In addition, daily intraperitoneal administration of cinnamaldehyde, a TRPA1 agonist, ameliorated BCAS-induced cognitive impairment and white matter injury at 28 days after operation. These results suggest that TRPA1 plays a protective role in the development of CCH-induced cognitive impairment and white matter injury, and that TRPA1 may be a therapeutic target for CCH-related CNS diseases.