Published Online
on March 20, 2003

A more recent version of this article appeared on April 1, 2003

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Submitted on October 9, 2002
Accepted on November 4, 2002

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

Takashi Horiguchi MD^*; Bela Kis PhD; Nishadi Rajapakse BS; Katsuyoshi Shimizu MD; and David W. Busija PhD

From the Department of Physiology and Pharmacology (T.H., B.K., N.R., D.W.B.) and Molecular Medicine Graduate Program (N.R.), Wake Forest University School of Medicine, Winston-Salem, NC, and Department of Neurosurgery, Tachikawa Hospital, Tokyo, Japan (K.S.).

^* To whom correspondence should be addressed. E-mail: takaholy{at}aol.com.

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 (_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 _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.

Key words: brain ischemia • middle cerebral artery occlusion • mitochondria • potassium channels • rats

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