Opening of Mitochondrial ATP-Sensitive Potassium Channels Is a Trigger of 3-Nitropropionic Acid–Induced Tolerance to Transient Focal Cerebral Ischemia in Rats

Abstract

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; nϭ16) or vehicle (saline; nϭ16) 3 days before temporary occlusion (120 minutes) of the middle cerebral artery; 5-HD (40 mg/kg IP; nϭ16) 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 mol/L 3-NPA-induced alterations of mitochondrial membrane potential (⌬⌿ m ) in cultured neurons and astrocytes using the fluorescent dye tetramethylrhodamine ethyl ester. Results-Treatment with 3-NPA exhibited a 16% reduction (PϽ0.05) and 23% reduction in infarct volume (PϽ0.01) 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 ⌬⌿ 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.

Effect of MPTP on mRNA expression of PGC-1α in mouse brain

“…This approach has already been demonstrated to be beneficial in case of 3-NP: the low-dose of toxin treatment increased the tolerance to ischemia and hypoxia in rats and gerbils (Horiguchi et al, 2003;Riepe et al, 1997;Wiegand et al, 1999). Although the exact mechanism in the background is not fully understood, the overexpression of free radical scavenging enzymes may be involved: acute 3-NP treatment activated superoxide dismutase (SOD) and catalase (CAT) in several brain areas (Binienda et al, 1998).…”

Evidence for Mitochondrial K + Channels and Their Role in Cardioprotection

“…Studies in heart 67 and brain 68 have suggested that enhanced tolerance to ischemia conferred by the SDH inhibitor 3-nitropriopionic acid might involve mitoK ATP opening, as evidenced by attenuation of the protection by 5-HD. Recent experiments suggest that 3-nitropriopionic acid activates mitoK ATP channels reconstituted from a highly purified mitochondrial membrane preparation, 69 and this effect was inhibited by 5-HD or glibenclamide, implying that SDH modulates mitoK ATP as part of a macromolecular complex.…”

Stimulation of neuronal KATP channels by cGMP-dependent protein kinase: involvement of ROS and 5-hydroxydecanoate-sensitive factors in signal transduction

“…To test this possibility, we pretreated transfected HEK293 cells with the mitoK ATP channel inhibitor 5-HD (100 M) for at least 15 min, followed by cell-attached patch recordings of Kir6.2/SUR1 channels before and during application of zaprinast (50 M) in the continuous presence of 5-HD (100 M). 5-HD, a natural lipid component of human milk, has been shown to disrupt ischemic tolerance conferred by ischemic and pharmacological preconditioning in heart and brain, which action is thought to result from inhibition of mitoK ATP channels (31,49). We found that zaprinast did not induce an increase in the single-channel activity of Kir6.2/SUR1 channels when 5-HD was coapplied (Fig.…”