CEREBROPROTECTIVE EFFECTS OF AMINOGUANIDINE IN A RODENT MODEL OF STROKE

Background and Purpose During a cerebral infarction, a complex cascade of cytotoxic events ultimately determines the volume of brain cell lo ss. The studies presented here demonstrate that aminoguanidine, an exp erimental therapeutic currently in clinical trials to prevent diabetic complications, is cerebroprotective in focal cerebral infarction. Met hods Adult Lewis rats (n=6 to 12 per group)were anesthetized with keta mine and subjected to focal cerebral infarction by tandem permanent oc clusion of the right middle cerebral artery and ipsilateral common car otid artery (CCA), followed by temporary occlusion of the contralatera l CCA. Infarct volume (cortical) was assessed 24 hours after the onset of ischemia by planimetric analysis of coronal brain slices stained w ith tetrazolium. Results Aminoguanidine (320 mg/kg IP) administered 15 minutes after the onset of ischemia resulted in a significant reducti on of infarct volume (7.6+/-2.6% of hemisphere in controls versus 1.3/-0.2% of hemisphere in aminoguanidine-treated rats; P<.05). Administr ation of aminoguanidine conferred significant cerebroprotection even w hen administered 1 or 2 hours after the onset of ischemia (88% and 85% reduction from control, respectively; P<.05). Cerebroprotection by am inoguanidine was independent of systemic physiological variables known to influence stroke size leg, temperature, mean arterial blood pressu re, blood glucose, and arterial pH, PCO2, and PO2). Conclusions These results indicate that the stroke-reducing properties of aminoguanidine are dose and time dependent, with substantial cerebroprotection persi sting even with drug delivery up to 2 hours after the onset of ischemi a. It is now plausible to pursue development of aminoguanidine as an e xperimental therapeutic in stroke, and possible mechanisms of these ce rebroprotective effects are under consideration.