kr-31378 and Brain-Edema

Neuronal hyperexcitability and oxidative stress play critical roles in neuronal cell death in stroke. Therefore, we studied the effects 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), possessing both antioxidant and K(+) channel-modulating activities, on brain ischemia-reperfusion injury models. Treatment with KR-31378 (30 mg/kg, i.v.) significantly reduced infarct area and edema by 24% and 36%, respectively, in rats subjected to 2 h of middle cerebral artery occlusion and 22 h of reperfusion with significant attenuation of elevated lipid peroxidation (99% of normal) and glutathione loss (60% of normal) in ischemic hemisphere. We further studied its neuroprotective mechanism in fetal rat primary mixed cortical culture. Incubation of cortical neurons with KR-31378 protected FeSO(4)-induced cell death in a concentration-dependent manner (IC(50)=12 microM). Its neuroprotective effect was neither mimicked by other K(+) channel openers nor abolished in the presence of ATP-dependent K(+) channel (K(ATP)) blockers, indicating that its effect was not related to K(+) channel opening activity. The mechanism of protection is rather attributable to the antioxidant property of KR-31378 since it suppressed the intracellular accumulation of reactive oxygen species and ensured lipid peroxidation by 120% and 80%, respectively, caused by FeSO(4). We further studied its effect on antioxidant defense, enzymatic and nonenzymatic systems. Treatment of neurons with FeSO(4) resulted in decrease of catalase (8% of control) and glutathione peroxidase (14% of control) activities, which were restored by KR-31378 treatment (70% and 57% of control, respectively). In addition, it attenuated the depletion of glutathione contents (60% of control) caused by FeSO(4). These results suggest that KR-31378 exerts a beneficial effect in focal ischemia, which may be attributed to its antioxidant property.

Topics: Animals; Antioxidants; Astrocytes; Brain Edema; Cell Death; Cells, Cultured; Cerebral Cortex; Free Radicals; Glutathione; Guanidines; Infarction, Middle Cerebral Artery; Iron; Lipid Peroxidation; Male; Neurons; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress; Potassium Channels; Pyrans; Rats; Rats, Sprague-Dawley; Reperfusion Injury