Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats

Background and Purpose - The role of mitochondrial ATP-sensitive potassium channels (mitoK_ATP) in ischemic tolerance has been well documented in heart, but little work has been done in brain. To investigate the involvement of mitoK_ATP activation in chemical preconditioning in brain, we examined the effect of 5-hydroxydecanoate (5-HD), a selective mitoK_ATP blocker, on neurotoxin 3-nitropropionic acid (3-NPA)-induced ischemic tolerance to transient focal cerebral ischemia in rats. Methods - Male Wistar rats were administrated 3-NPA (20 mg/kg IP; n = 16) or vehicle (saline; n = 16) 3 days before temporary occlusion (120 minutes) of the middle cerebral artery; 5-HD (40 mg/kg IP; n = 16) was injected 20 minutes before 3-NPA administration. Infarct volumes were measured 4 days after reperfusion. To directly investigate whether chemical preconditioning activates mitoK_ATP, we tested the effect of prior incubation with 1 mmol/L 5-HD on 300 μmol/L 3-NPA-induced alterations of mitochondrial membrane potential (ΔΨ_m) in cultured neurons and astrocytes using the fluorescent dye tetramethylrhodamine ethyl ester. Results - Treatment with 3-NPA exhibited a 16% reduction (P<0.05) and 23% reduction in infarct volume (P<0.01) for total brain and cortex, respectively. Pretreatment with 5-HD completely abolished the neuroprotective effect of chemical preconditioning. In cultured cells, 3-NPA resulted in mitochondrial depolarization. This change of ΔΨ_m was completely blocked by 5-HD pretreatment. Conclusions - These results strongly suggest that opening of mitoK_ATP plays a key role as the trigger in the development of 3-NPA-induced ischemic tolerance in brain.