Involvement of mitoKATP channel in protective mechanisms of cerebral ischemic tolerance.
Little work has been performed to determine roles of mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) in ischemic preconditioning (IPC) in brain. To investigate the role on cerebral IPC, we examined effect of 5-hydroxydecanoate (5-HD), a selective mitoK(ATP) blocker, and diazoxide (DZX), a selective mitoK(ATP) opener on various IPC models. An IPC model with gerbil: 2 min bilateral common carotid arteries occlusion (BLCO)+24 h recovery+5 min BLCO. 5-HD, DZX, vehicle was administered 30 min before 5 min BLCO. Seven days later, surviving CA1 neurons were counted. A focal IPC model with rat: 15 min middle cerebral artery occlusion (MCAO)+48 h recovery+90 min MCAO. Twenty-four hours before 90 min MCAO, 5-HD, DZX, or vehicle was administered. One day after 90 min MCAO, neurological symptoms and infarct volumes were evaluated. An in vitro IPC model with primary neuronal cultures: 8 min oxygen-glucose deprivation (OGD)+24 h recovery+70 min OGD. Thirty minutes before 70 min OGD, 5-HD or DZX were added. One day later, surviving neurons were counted. Mitochondrial membrane potential was also monitored. 5-HD significantly attenuated the protective effect of IPC in gerbil model, rat model, and in vitro OGD model. DZX significantly facilitated the protective effect of IPC in gerbil and rat model. The mitochondrial membranes were depolarized with IPC, and 5-HD treatment significantly reduced this effect. These results strongly suggest that mitoK(ATP) channel activation plays a key role in development of a protective mechanism of cerebral IPC.
Watanabe
Megumi
M
Department of Internal Medicine, Division of Neurology, Nippon Medical School, Tokyo, Japan.
Katsura
Ken-ichiro
K
Ohsawa
Ikuroh
I
Mizukoshi
Genki
G
Takahashi
Kumiko
K
Asoh
Sadamitsu
S
Ohta
Shigeo
S
Katayama
Yasuo
Y
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D005849:Gerbillinae; D006880:Hydroxy Acids / Q000494:pharmacology; D019194:Ischemic Preconditioning; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D015221:Potassium Channels; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; D003981:Diazoxide