Novel Pharmacological Approach to Stroke Neuroprotection

Diabetic patients (Type2) are not only at a 2 to 6-fold higher risk for having acute ischemic stroke, but also suffer from neurovascular complications, including blood-brain barrier-BBB leakage, edema and hemorrhage and poor recovery after ischemic stroke. Despite recent advances, interventions to mitigate these risks after stroke are high research priority. Disruption in normal calcium homeostasis is a major initiator and contributor to diabetes induced ischemic brain injury. SERCA2 (sarco/endoplasmic reticulum Ca2+ ATPase pump) is an important regulator of intracellular Ca2+ concentration. Diabetes and stroke reduce SERCA2 expression and function, increase cytosolic Ca2+ concentration, and subsequently enhance cell death and tissue damage associated with endoplasmic reticulum (ER) stress, mitochondrial dysfunction, inflammation, and oxidative stress. Thus, targeting dysfunctional SERCA2 could be a potential therapeutic opportunity to alleviate neurovascular complications associated with diabetes in stroke. In this proposal we will investigate the beneficial effect and the mechanisms of our newly developed small molecular SERCA2 activator CDN1163 for treating neurovascular complications associated with diabetes comorbidity in stroke. Our preliminary data show diabetic (Ob/ob) and wild-type (WT) mice have lower SERCA2 expression after stroke, while treatment with CDN1163 reduced infarct volume and functional deficits after stroke. Based on our solid scientific publications and compelling preliminary observations, our central hypothesis is that SERCA2 activation after stroke will restore diabetes associated Ca2+ dysregulation and attenuate ER stress, mitochondrial dysfunction, and, subsequently, neurovascular, and functional recovery. Using comprehensive, novel approaches with state-of-the-art in vivo and in vitro, models, molecular biological, approaches, including comprehensive single-cell RNAseq transcriptional regulation, this project explores the underlying cellular and molecular mechanisms driving CDN neuroprotection in diabetic stroke injury.