Clemastine ameliorates cognitive deficits in an experimental rat model of chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion (CCH) profoundly affects patient well-being and has been proposed as a risk factor for cognitive impairment and dementia. However, due to the limited understanding of the pathophysiology of CCH, there are currently no effective preventive or therapeutic approaches for CCH-associated cognitive impairment. Therefore, identifying new targets for CCH is essential to bridge this knowledge gap. In this study, we sought to determine whether enhanced myelination could prevent cognitive impairment associated with CCH. Experimental CCH was induced via bilateral common carotid artery occlusion (BCCAO) in rats, and clemastine, a well-established pro-myelinating agent, was administered to boost myelin renewal. A series of behavioral tests was performed to assess learning and memory. We found that animals exhibited profound cognitive deficits 3 months after BCCAO, accompanied by significant myelin loss, structural disruption at the nodes of Ranvier, and synaptic dysfunction in various brain regions, without notable neuronal loss and oligodendrocyte apoptosis. Importantly, pharmacological enhancement of myelination preserved dendritic spine density and prevented synaptic loss, cognitive deficits, and neurovascular dysfunction following BCCAO. These findings suggest that clemastine may represent a promising therapeutic option for CCH-associated cognitive impairment.