Apocynin may limit total cell death following cerebral ischemia and reperfusion by enhancing apoptosis

Abstract

The present study was designed to determine a dose-response relationship between apocynin and infarct volume as well as to provide a possible molecular mechanism mediating this effect. We tested the hypothesis that apocynin protects against cell death following stroke and reperfusion injury. Apocynin was administered 30 min prior to, or immediately following removal of sutures used to occlude the middle cerebral artery (MCA) in male Sprague-Dawley rats. Following removal of the sutures, the MCA was allowed to undergo 5.5h of reperfusion. Pretreatment with apocynin 30 min prior to occlusion resulted in a dose-dependent reduction in infarct volume by ∼50 %. Analysis of tissue from the ischemic cortex of apocynin-treated rats showed an increase in the level of glutathione (GSH), protein adducts (HNE-His), hydrogen peroxide (H(2)O(2)) and DNA fragmentation (apoptotic cell death) was also observed. This suggests that apocynin may increase antioxidant defense systems (GSH) to limit the degree of ischemia-induced cellular stress. In addition, this moderate cell stress results in more apoptotic vs necrotic cell death, and thus may limit the spreading depression and total cell death that occurs following ischemia/reperfusion. These effects may serve as a potential novel mechanism of action contributing to the apocynin-induced neuroprotection observed.