Alteration of ischemic reperfusion injury in the rat neocortex by a potent antioxidant mexiletine.

ABSTRACT

The mechanisms by which mexiletine exerts its effects in increasing myocardial circulation, and smooth muscle perfusion and alleviating diabetic neuropathic pain have been widely discussed. The purpose of this study was to examine the protective effect of this compound in ischemia/reperfusion-induced cerebral injury following middle cerebral artery occlusion in Sprague-Dawley rats. Blood flow to the left cerebral hemisphere of the animals was interrupted by occluding the left cerebral artery and both carotid arteries simultaneously for 3 hrs. These animals were assigned to one of ten groups and divided into treatment group and pretreatment group; 1) control treatment group (n=8); 2) vehicle treatment group (n=8); 3) lower dose mexiletine (400 microg/kg) treatment group (n=8); 4) medium dose mexiletine (800 microg/kg) treatment group (n=8); 5) high dose mexiletine (2 mg/kg) treatment group (n=8); 6) control pretreatment group (n=8); 7) vehicle pretreatment group (n=8); 8) lower dose mexiletine (400 microg/kg) pretreatment group (n=8); 9) medium dose mexiletine (800 microg/kg) pretreatment group (n=8); and 10) high dose mexiletine (2 mg/kg) pretreatment group (n=8). The volume of cerebral infarction was measured in serial brain sections stained with triphenyltetrazolium chloride (TTC). Tissue infarction volume and tissue edema were estimated for each animal. The volume of cerebral infarction was significantly decreased in rats pretreated with mexiletine, and the ratio of tissue edema was also decreased as the dose of mexiletine increased. These results demonstrate that mexiletine, an anti-arrhythmic and use-dependent Na+ channel blocker, has protective effects in stroke at concentrations sufficient to confer significant protection, as measured by the volume of infarction and brain edema index in a model of focal, neocortical ischemia in Sprague-Dawley rats.