Cinnamaldehyde improves the pathology of vascular cognitive impairment via astrocytic TRPA1

Vascular cognitive impairment (VCI) comprises cognitive dysfunction caused by vascular pathology and is associated with various forms of dementia. VCI is typically caused by chronic cerebral hypoperfusion (CCH), which is accompanied by oxidative stress, central nervous system inflammation, microglial activation, and white matter injury. Therapeutic targets for VCI remain largely unknown. Transient receptor potential ankyrin 1 (TRPA1) is functionally expressed in the brain, where it senses changes in oxygen levels and is activated by hypoxia and hyperoxia. We investigated the pathophysiological roles of TRPA1 stimulation during late-stage CCH that was induced using bilateral common carotid artery stenosis (BCAS) in a mouse model of VCI. Cinnamaldehyde-induced TRPA1 stimulation improved CCH-induced white matter injury and cognitive impairment. However, cinnamaldehyde failed to improve CCH-related outcomes in astrocyte-specific TRPA1-deficient mice, which indicated that the protective effects of cinnamaldehyde are mediated by astrocytic TRPA1. The administration of cinnamaldehyde suppressed the CCH-induced increase in Iba1-positive microglia. These results suggest that the activation of astrocytic TRPA1 by cinnamaldehyde contributes to disease amelioration in advanced stages of VCI, potentially through astrocyte-derived factors, including leukemia inhibitory factor, IL6 family cytokines, and other mediators, that suppress microglial activation.