Stroke is a major cause of death and disability in the United States. Evidence suggests that even if blood flow is initially restored additional """"""""reperfusion injury"""""""" processes can occur that can potentiate brain injury and reduce existing blood flow. Some of the mediators of this """"""""reperfusion injury"""""""" appear to be due to an inflammatory responsive involving free radical generation, activated leukocytes, and platelet activated factor. Various commercially available """"""""antioxidant supplements"""""""" appear to produce clinical benefit in several diseases. These supplements including Ginkgo biloba extract (EGb) and alpha lipoic acid (LA) have multitude of biologic effects including reducing free radical generation, inhibiting PAF and leukocyte activation (inhibit NFalphaB), and improving cerebral blood flow. Antioxidants have shown benefits in multiple disease models involving reperfusion injury but have yet to be fully evaluated in reperfusion injury related to stroke. This project will investigate the treatment potential and protective mechanisms of selected antioxidants using an animal model that closely approximates clinical stroke.
The specific aims of the study are as follows:
Aim 1 : To confirm and characterize the neuroprotective efficacy of EGb in focal CNS ischemia, determine the effects of EGb on the inflammatory response and CBF, and evaluate safety interventions with other medications used in stroke.
Aim 2 : To confirm and characterize the neuroprotective efficacy of LA and dihydro lipoic (DHLA) in focal CNS ischemia and determine their effects on the inflammatory response and CBF. This study will use the middle cerebral artery filament occlusion (MCAO) model in the mouse and will utilize a combination of ischemic damage (lesion size) and neurologic functional measurements to determine efficacy. Potential mechanisms of efficacy for each antioxidant will be assessed including effects on in vivo cerebral blood flow (laser doppler measurement of blood flow) and the inflammatory response (molecular and flow cytometry). The information obtained from this project will be critical in planning future clinical stroke trials involving these agents.
