Role of a synthetic pyrimidine compound, MS-818, in reduction of infarct size and amelioration of sensorimotor dysfunction following permanent focal cerebral ischemia in rats.

Abstract

A synthetic heterocyclic pyrimidine compound, MS-818 (2-piperadino-6-methyl-5-oxo-5,6-dihydro-(7H) pyrrolo-[3,4-d] pyrimidine maleate) is reported to have a variety of biological activities including neurite outgrowth, astrocyte differentiation, suppression of neuronal apoptosis, regeneration of injured peripheral nerves, fracture repairs, angiogenesis, and superovulation. To be able to explicate the neurotrophic effects of MS-818, the authors evaluated its effect on the reduction of infarct volume and amelioration of sensorimotor dysfunction in a rat model of focal ischemia. Forty male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion and assigned to one of four treatment groups (10 animals in each group). The MS-818 (1, 5, or 10 mg/kg) or phosphate-buffered saline (control group) was administered intraperitoneally at onset of ischemia and again 24 hours later. The rats were killed 48 hours after they underwent surgery to induce stroke, and infarct volume was determined using an image-analysis computer software program following staining with 2,3,5-triphenyltetrazolium chloride. Postischemic neurological deficit and body weight were also assessed. Significant reductions in infarct volume (total and cortical infarction) were found in all the MS-818-treated groups compared with the control group. Furthermore, MS-818 induced significant amelioration of sensorimotor dysfunction, as indicated by the results of forelimb and hindlimb placing tests. The present findings suggest that MS-818, which has a much smaller molecular weight than neurotrophic peptides. represents a new approach to the treatment of focal cerebral ischemia.