MitoKATP-channel opener protects against neuronal death in rat venous ischemia.
OBJECTIVE
Mitochondrial adenosine triphosphate-dependent potassium (mitoKATP) channels are present in the brain, and several reports have shown their neuroprotective, preconditioning effect against an ischemic insult. The role of mitoKATP channels in the penumbra area has not been studied thoroughly. In a model of venous ischemia, widespread penumbra-like low flow areas are created, which are susceptible to cortical spreading depression. Thus, we studied effects of mitoKATP channels on infarct size in this model.


METHODS
Male Wistar rats were subjected to two-vein occlusion by photochemical thrombosis of two adjacent cortical veins combined with KCl-induced cortical spreading depression. The rats were assigned to four experimental groups pretreated intraventricularly 15 minutes before two-vein occlusion with 1) vehicle, 2) the mitoKATP channel opener diazoxide (2 mmol/L), 3) diazoxide (2 mmol/L) plus the selective mitoKATP channel blocker 5-hydroxydecanoate (5-HD; 100 mmol/L), or 4) 5-HD alone (100 mmol/L). Regional cerebral blood flow (laser Doppler scanning) and brain cell swelling (impedance) were monitored acutely. Infarct volume was assessed 7 days after ischemia.


RESULTS
Pretreatment with diazoxide significantly reduced the infarct volume from 6.2 +/- 0.7 mm3 to 3.8 +/- 0.4 mm3, whereas regional cerebral blood flow in the vicinity of the two veins was comparable in both groups 70 minutes after two-vein occlusion. Effects of diazoxide were abolished by 5-HD, whereas 5-HD alone even increased infarct volume.


CONCLUSIONS
These results suggest that the opening of mitoKATP channels plays a major role in brain protection under penumbra-like conditions, as shown in this venous occlusion model.
Nakagawa
Ichiro
I
Institute for Neurosurgical Pathophysiology, Johannes Gutenberg University, Mainz, Germany.
Alessandri
Beat
B
Heimann
Axel
A
Kempski
Oliver
O
D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002550:Cerebral Veins / Q000503:physiopathology*; D013181:Cortical Spreading Depression / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000627:therapeutic use; D004195:Disease Models, Animal; D004347:Drug Interactions; D006880:Hydroxy Acids / Q000494:pharmacology; D007511:Ischemia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010777:Photochemistry / Q000379:methods; D015221:Potassium Channels / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D018696:Neuroprotective Agents; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; D011189:Potassium Chloride; D003981:Diazoxide