Abstracts

Mitochondria play a central role in energy production and processes of cell death. These organelles also regulate Ca²⁺ homeostasis, and thereby modulate neuronal excitability and synaptic transmission. More recently, mitochondrial dysfunction has been shown to occur in seizure foci from humans and experimental models of epilepsy. In addition, a number mitochondrial DNA mutations have been identified which lead to the inhibition of the mitochondrial respiratory chain. Because neuronal injury during prolonged seizure activity may occur via modulation of mitochondrial channels and mitochondrial membrane depolarization, we hypothesized that the opening of mitochondrial ATP-sensitive potassium (mitoK[sub]ATP[/sub]) channels would provide protection against CA1 depolarization-induced injury. Using paired rat hippocampal slices, we monitored the CA1 orthodromic and antidromic population spike (PS) amplitude during depolarization injury with and without calcineurin inhibitor treatment. To induce depolarization injury, slices were exposed to 25 mM KCl for 8 min. Treatment with diazoxide was begun 30 minutes prior to KCl exposure and continued for the first 15 min. of recovery. Diazoxide, a mitoK[sub]ATP[/sub] channel opener, provided robust neuroprotection of CA1 PS amplitude in hippocampal slices subjected to depolarization-induced injury. Slices exposed to 25 mM KCl demonstrated rapid loss of evoked response with a mean CA1 orthodromic and antidromic recovery of only 11% [plusmn] 3 and 13% [plusmn] 2, respectively. Treatment with diazoxide (100 uM) provided significant protection against this depolarization injury with CA1 orthodromic and antidromic PS amplitude recovering to 94% [plusmn] 3 and 95% [plusmn] 3. Treatment with 100 uM diazoxide during depolarization injury also produced significant recovery of mean excitatory post-synaptic potential slope (94% [plusmn] 6) after depolarization when compared to paired, unmedicated slices which did not recover (0% [plusmn] 0). Mean fiber volley responses were slightly resistant to depolarization injury with a mean recovery of 32% [plusmn] 2 in paired, unmedicated slices. In contrast, treatment with diazoxide showed full recovery with a mean 100% [plusmn] 0. These studies demonstrate that diazoxide, a mitoK[sub]ATP[/sub] channel opener provides neuroprotection against CA1 depolarization injury. In addition, these data suggest that the use of agents that modulate the mitoK[sub]ATP[/sub] channel may provide a useful strategy in the prevention of brain injury during status epilepticus. (Supported by VA Research Service and the UCLA Brain Injury Research Center.)