Activation of mitochondrial ATP-sensitive potassium channels prevents neuronal cell death after ischemia in neonatal rats

Abstract

Activation of mitochondrial ATP-sensitive potassium channels (mK ATP) has been shown to protect against cell death following ischemia/reperfusion in the heart but not in brain. We examined whether mK ATP activation with diazoxide (DIZ) prevents neuronal cell death following hypoxia-ischemia (HI) in 7-day-old rat pups. Rat pups were subjected to HI (left carotid ligation; 8% O 2; 2.5 h), following administration of vehicle, 1.9 mg/kg DIZ, 3.8 mg/kg DIZ or DIZ plus 10 mg/kg 5-hydroxydecanoic acid (mK ATP antagonist). Total infarct volume was reduced from 99.8±2.7% in vehicle animals to 80.6±4.2% in 3.8 mg/kg DIZ treated animals ( n=85, P<0.05). Western blotting showed K ATP subunits concentrated in mitochondria. Fluorescent studies indicated DIZ directly depolarized the mitochondria. In conclusion, selective opening of mK ATP prior to HI results in neuroprotection in immature rats.