A Small-Molecule Activator of Sarco/Endoplasmic Reticulum Ca2+-ATPase Attenuates Cerebral Ischemia–Reperfusion Injury by Suppressing Endoplasmic Reticulum Stress and Apoptosis

Abstract

Calcium (Ca²⁺) homeostasis is critical for neuronal survival and function, which is regulated by a network of Ca²⁺-handling proteins. Among these, the sarco/endoplasmic reticulum calcium ATPase (SERCA) pump, located on the SR/ER membrane, plays a pivotal role in sequestering Ca²⁺ into the ER, thereby maintaining low cytosolic Ca²⁺ levels. Dysregulated SERCA function during ischemia contributes to ER Ca²⁺ depletion, resulting in intracellular Ca²⁺ imbalance and ER stress, both of which are implicated in the pathogenesis of ischemic reperfusion injury; SERCA has thus emerged as a potential pharmacological target for ischemic stroke. CDN1163, a SERCA activator, has shown promising effects in preclinical studies of neurodegenerative diseases by alleviating ER stress and restoring the Ca²⁺ balance. This study investigates the neuroprotective potential of CDN1163 against cerebral ischemia-reperfusion (IR) injury using middle cerebral artery occlusion (MCAO) in rats. CDN1163 treatment (10 mg/kg, i.p.) significantly improved neurological scores, motor function, and behavior, while reducing infarct volume, brain edema, and oxidative stress by decreasing nitrite and lipid peroxidation and restoring glutathione levels. Histological analysis revealed reduced neuronal damage in the cortex, subcortex, and hippocampus regions. CDN1163 restored SERCA2b and 1a expression and mitigated ER stress by decreasing the expression of ER stress markers, such as PDI, BiP, p-IRE1α, XBP1, p-PERK, p-eIF2α, ATF4, and ATF6. Furthermore, CDN1163 downregulated pro-apoptotic markers Bax and CHOP, while upregulating the antiapoptotic protein Bcl-2 with TUNEL assay confirming decreased apoptosis. These outcomes highlight that CDN1163 is a potential therapeutic candidate for ischemic stroke, as it restores SERCA expression, alleviates endoplasmic reticulum stress, reduces oxidative stress, and inhibits apoptosis.