The mitochondrial K(ATP) channel opener BMS-191095 reduces neuronal damage after transient focal cerebral ischemia in rats.

Abstract

Activation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels protects the brain against ischemic or chemical challenge. Unfortunately, the prototype mitoK(ATP) channel opener, diazoxide, has mitoK(ATP) channel-independent actions. We examined the effects of BMS-191095, a novel selective mitoK(ATP) channel opener, on transient ischemia induced by middle cerebral artery occlusion (MCAO) in rats. Male Wister rats were subjected to 90 mins of MCAO. BMS-191095 (25 microg; estimated brain concentration of 40 micromol/L) or vehicle was infused intraventricularly before the onset of ischemia. In addition, the effects of BMS-191095 on plasma and mitochondrial membrane potentials and reactive oxygen species (ROS) production in cultured neurons were examined. Finally, we determined the effects of BMS-191095 on cerebral blood flow (CBF) and potassium currents in cerebrovascular myocytes. Treatment with BMS-191095 24 h before the onset of ischemia reduced total infarct volume by 32% and cortical infarct volume by 38%. However, BMS-191095 administered 30 or 60 mins before MCAO had no effect. The protective effects of BMS-191095 were prevented by co-treatment with 5-hydroxydecanoate (5-HD), a mitoK(ATP) channel antagonist. In cultured neurons, BMS-191095 (40 micromol/L) depolarized the mitochondria without affecting ROS levels, and this effect was inhibited by 5-HD. BMS-191095, similar to the vehicle, caused an unexplained but modest reduction in the CBF. Importantly, BMS-191095 did not affect either the potassium currents in cerebrovascular myocytes or the plasma membrane potential of neurons. Thus, BMS-191095 afforded protection against cerebral ischemia by delayed preconditioning via selective opening of mitoK(ATP) channels and without ROS generation.

• Authors: Keita Mayanagi, Tamás Gáspár, Prasad V G Katakam, Béla Kis, David W Busija
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 27 Issue 2 Pg. 348-55 (Feb 2007) ISSN: 0271-678X [Print] United States
• PMID: 16736040 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BMS 191095
• Benzimidazoles
• Benzopyrans
• Imidazoles
• Neuroprotective Agents
• Potassium Channels
• Reactive Oxygen Species
• mitochondrial K(ATP) channel
• NS 1619

Topics

• Animals
• Benzimidazoles (pharmacology)
• Benzopyrans (pharmacology)
• Cell Membrane (drug effects)
• Cells, Cultured
• Cerebral Arteries (cytology, drug effects, metabolism)
• Cerebrovascular Circulation (drug effects)
• Imidazoles (pharmacology)
• Infarction, Middle Cerebral Artery (pathology)
• Ischemic Attack, Transient (pathology)
• Male
• Membrane Potentials (drug effects)
• Mitochondrial Membranes (drug effects)
• Muscle Cells (drug effects, metabolism)
• Neuroprotective Agents
• Potassium Channels (agonists)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)