Abstract Body: Background: Ischemic stroke is a leading cause of high mortality and long-term disability. The current therapies for acute ischemic stroke remain limited to thrombolysis or thrombectomy, for which many patients are ineligible. Therefore, developing new treatments for stroke is a significant clinical need. Dysregulated calcium (Ca²⁺) homeostasis induces endoplasmic reticulum (ER) stress, mitochondrial dysfunction, microglial activation, inflammation, oxidative stress, and synaptic deficits implicated in stroke. Our recently developed molecular allosteric activator (CDN1163) of sarcoendoplasmic reticulum Ca^2+-ATPase (SERCA2) plays a vital role in calcium homeostasis, alleviates ER stress and has emerged as a potential therapeutic approach for metabolic disorder and brain protection. Thus, this study aimed to investigate the protective role of CDN1163 against ischemic stroke in mice.
Methods: Ischemic stroke was induced in adult male mice using the Rose Bengal photothrombosis method. CDN1163 (50mg/kg) was administered intraperitoneally at specific time points following the stroke. After 72 hours, the Catwalk test was performed to assess gait impairments. The mice were then euthanized, and their brain tissues were harvested for further analysis, including the measurement of infarct volume, brain edema, and molecular analysis. Neuronal apoptosis was determined using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeled (TUNEL) staining.
Results: CDN1163-treated mice showed a significant improvement in gait impairments and reduction in infarct volume and brain edema compared to the vehicle group. CDN1163 treatment also attenuated vascular damage by reducing immunoglobulin extravasation and restoring tight junction protein. In addition, CDN1163 treatment attenuated oxidative damage by reducing 4-hydroxynonenal and nitrotyrosine protein expression levels. Furthermore, the expression levels of apoptotic proteins and numbers of TUNEL-positive cells were significantly decreased in the CDN1163-treated group compared to the vehicle group (Table 1).
Conclusion: Our results indicate that CDN1163 reveals neuroprotection through attenuating vascular damage, oxidative stress, and neuronal loss against stroke pathogenesis. Further investigations into the therapeutic effects of CDN1163 are needed to determine whether it can be an effective therapeutic agent for stroke.