Friday, April 19, 2024
4/19/2024
Project Summary Cocaine use can lead to stroke and cerebral ischemia. There is an urgent public health need to develop safe and effective medications that can mitigate/reverse the effects of cocaine to reduce ischemic risk. However, there are no FDA-approved medications for cocaine use disorder. The goal of this proposal is to seek new therapeutic targets within astrocytes for cocaine use disorder treatment. We hypothesize that 1) chronic cocaine use can trigger astrocyte pathological responses and cell loss, which will lead to microvascular endothelial cell activation, inflammation and dysfunction, causing downstream cerebral blood flow reduction and hypoxia-ischemia; and 2) inhibiting iNOS (inducible nitric oxide synthase) upregulation in astrocytes using an iNOS inhibitor is an effective strategy to prevent cocaine- induced vascular inflammation and restore cerebral blood flow. To test these hypotheses, two specific aims will be carried out. Specific aim 1 is to explore astrocyte iNOS involvement in cocaine-induced neurovascular deficit in the prefrontal cortex. We will investigate how chronic cocaine exposure affects astrocytes and brain microvascular pathophysiology in the prefrontal cortex of mouse brain. Experimental mice will be treated daily with cocaine for two weeks, and control animals will be treated with saline. Optical imaging will be used to evaluate cocaine-induced deficits in cerebral blood flow and intracellular calcium changes in astrocytes; various biological assays including immunofluorescence microscopy, Western blot, and ELISA will be used to quantify astrocyte iNOS expression and cerebral microvascular endothelial cell inflammatory responses. In specific aim 2, we will examine the efficacy of iNOS (drug target) blocker in inhibiting excessive NO production, astrocytic Ca2+ release, and hemodynamic dysfunction induced by cocaine in the mouse prefrontal cortex. Therapeutic efficiency of iNOS blocker(s) will be evaluated. Similar experimental approaches (optical imaging and biological assays) will be used to evaluate iNOS inhibitor’s effects in astrocyte activation, apoptosis, calcium level, cerebral blood flow, microvascular endothelial cell activation and inflammatory protein expression. A cellular-molecular pathway that links astrocytes, endothelial cells and cerebral blood flow regulation will be validated. It is novel to use astrocytes as a drug target to treat cocaine use disorder. Results obtained from this study will significantly improve our current understanding of cocaine-induced hypofunction in the prefrontal cortex with addiction, and help with the identification of new drug target that can treat (or prevent) brain tissue damage in cocaine use disorder.
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