Neuroprotective Effect of (2S,3S,4R)-N"-cyano-N-(6-amino-3, 4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N′-benzylguanidine (KR-31378), a Benzopyran Analog, against Focal Ischemic Brain Damage in Rats

Abstract

This study shows the preventive effect of KR-31378 [(2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N′-benzylguanidine] against cerebral infarct via antioxidant and antiapoptotic actions evoked by subjecting rats to 2 h of occlusion of the left middle cerebral artery followed by 24 h of reperfusion. The brain infarct zone in the cortex and striatum of the left hemisphere was consistently identified in the cortex and striatum of the left hemisphere. The infarct area was significantly reduced after three intraperitoneal administrations of 10, 30, or 50 mg/kg KR-31378 at 5 min, 4 h, and 8 h after the completion of 2 h of ischemia. Treatment with KR-31378 (30 or 50 mg/kg) significantly reduced the increase in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells as well as strongly suppressed the laddered feature of DNA fragmentation in the lateral cortical tissue corresponding to the penumbra. The findings of samples from penumbral zone, which showed markedly reduced Bcl-2 protein level and increased Bax protein and cytochrome c release, were wholly reversed by treatment with KR-31378. In conclusion, postischemic treatment with KR-31378 provided significant levels of cortical neuroprotection in association with inhibition of apoptotic cell death through the up-regulation of Bcl-2 expression, and the down-regulation of Bax protein and cytochrome c release.