EFFECTIVE REDUCTION OF INFARCT VOLUME BY GAP JUNCTION BLOCKADE IN A RODENT MODEL OF STROKE

Several lines of evidence indicate that the extent of ischemic injury is not defined immediately after arterial occlusion, but that infarcti on expands over time. Episodes of spreading depression have been linke d to this secondary increase in infarct volume. Tissue bordering the i nfarction fails to repolarize following spreading depression and is in corporated into the lesion. The result is that ischemic infarctions ex pand stepwise after each episode of spreading depression. Another line of evidence has demonstrated that gap junction blockers effectively i nhibit spreading depression. These observations suggest that traffic o f potentially harmful cytosolic messengers between ischemic cells and surrounding nonischemic cells might cause amplification of injury in f ocal stroke. It is therefore conceivable that minimizing gap junction permeability might reduce final infarct volume. To test this hypothesi s, the authors pretreated rats with the gap junction blocker, octanol, before occluding the middle cerebral artery and compared the sizes of the ischemic lesions to those in rats that received the vehicle, dime thyl sulfoxide, prior to arterial occlusion. Histopathological analysi s was per formed 24 hours later. The 12 octanol-treated animals showed a significantly decreased mean infarction volume (80 +/- 16 mm(3)) co mpared with the nine control rats (148 +/- 9 mm(3)). In a separate set of experiments, the frequency of experimentally induced waves of spre ading depression was evaluated after octanol treatment. Octanol pretre atment resulted in complete inhibition in two of nine animals, transie nt inhibition in five, and no inhibition in two. The results indicate that gap junction inhibitors, when not limited by toxicity, have signi ficant therapeutic potential in the treatment of acute stroke.