Clemastine Reduces post-stroke Neurodegeneration by Alleviating Endoplasmic Reticulum stress-mediated Demyelination and Cognitive Impairment Through PERK/ATF4/CHOP Signaling Pathway

Abstract

The progressive brain damage following ischemic stroke is primarily due to oxidative stress and activation of inflammatory pathways. Post-stroke neurodegeneration can lead to the loss of neurons and glial cells, including oligodendrocytes, contributing to demyelination. Following ischemic stroke, reperfusion results in increased intracellular calcium, generation of free radicals, and inflammation culminating in accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen augmenting the ER stress. ER stress has been shown to aggravate post-stroke neurodegeneration by triggering neuronal apoptosis and also contributing towards demyelination of neurons. To address the limitations of current stroke therapies, repurposing of drugs as future adjunctive therapy may be promising. Clemastine, an antihistaminic drug, improves post stroke outcome as evident in the present study. Male Sprague Dawley (SD) rats were treated with clemastine following ischemic stroke. Harvested brain tissues were subjected to different biochemical assays, molecular assays, and histopathological analysis. Clemastine was able to reduce infarct size, alleviate oxidative stress, improve neuronal count, and functional outcomes. Clemastine downregulated genes and proteins responsible for ER stress, apoptosis and demyelination as shown by the western blot and qPCR results. Our study suggests that clemastine may alleviate endoplasmic reticulum stress-mediated demyelination by modulating PERK/ATF4/CHOP axis, and may be used as one of the adjunctive therapies for stroke in future.

Keywords: Demyelination; Endoplasmic reticulum stress; Ischemic stroke; Neurodegeneration; Unfolded protein response.