Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats.
OBJECTIVE
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 micromol/L 3-NPA-induced alterations of mitochondrial membrane potential (Delta(Psi)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 Delta(Psi)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.
Horiguchi
Takashi
T
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1083, USA. takaholy@aol.com
Kis
Bela
B
Rajapakse
Nishadi
N
Shimizu
Katsuyoshi
K
Busija
David W
DW
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply; D003652:Decanoic Acids / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000503:physiopathology / Q000517:prevention & control*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D009574:Nitro Compounds; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011422:Propionates / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow
D003652:Decanoic Acids; D006880:Hydroxy Acids; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011422:Propionates; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; C015392:3-nitropropionic acid; D005905:Glyburide