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, Bela Kis, Nishadi Rajapakse, Katsuyoshi Shimizu, David W. Busija

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Abstract

Background and Purpose - The role of mitochondrial ATP-sensitive potassium channels (mitoKATP) in ischemic tolerance has been well documented in heart, but little work has been done in brain. To investigate the involvement of mitoKATP activation in chemical preconditioning in brain, we examined the effect of 5-hydroxydecanoate (5-HD), a selective mitoKATP 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 mitoKATP, 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 (ΔΨm) 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 ΔΨm was completely blocked by 5-HD pretreatment. Conclusions - These results strongly suggest that opening of mitoKATP plays a key role as the trigger in the development of 3-NPA-induced ischemic tolerance in brain.

Original languageEnglish
Pages (from-to)1015-1020
Number of pages6
JournalStroke
Volume34
Issue number4
DOIs
Publication statusPublished - 2003 Apr 1

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Keywords

  • Brain ischemia
  • Middle cerebral artery occlusion
  • Mitochondria
  • Potassium channels
  • Rats

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialised Nursing

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