Abstracts

Rationale: 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. Additionally, neuronal injury from prolonged seizure activity, mitochondrial membrane depolarization has been shown to occur. Therefore, we hypothesized that the opening of mitochondrial ATP-sensitive potassium (mito-KATP) channels would provide protection against CA1 depolarization-induced injury.Methods: Using paired rat hippocampal slices, we monitored the CA1 orthodromic and antidromic population spike (PS) amplitude during depolarization injury with and without nicorandil treatment. To induce depolarization injury, slices were exposed to 25 mM KCl for 8 min. Treatment with 100 uM nicorandil was begun 30 minutes prior to KCl exposure and continued for the first 15 min. of recovery. Results: Nicorandil, a mito-KATP 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 10% ± 2 and 12% ± 2, respectively. Treatment with nicorandil (100 uM) provided significant protection against this depolarization injury with CA1 orthodromic and antidromic PS amplitude recovering to 92% ± 3 and 93% ± 3. Treatment with 100 uM nicorandil during depolarization injury also produced significant recovery of mean excitatory post-synaptic potential slope (100% ± 0) after depolarization when compared to paired, unmedicated slices which did not recover (0% ± 0). Mean fiber volley responses were slightly resistant to depolarization injury with a mean recovery of 36% ± 3 in paired, unmedicated slices. In contrast, treatment with nicorandil showed full recovery with a mean 100% ± 0. Long-term-potentiation (LTP) after depolarization injury was initiated by tetnus stimulation of 100 Hz for 1 second. LTP was completely lost following depolarization injury, while treatment with nicorandil preserved LTP. With nicorandil treatment, tetanus after depolarization injury induced a mean increase in CA1 orthodromic PS amplitude to 131% ± 3, similar to LTP induced in untreated slices, which showed an increase of 132% ± 3. Conclusions: These studies demonstrate that nicorandil, a mito-KATP channel opener provides neuroprotection against CA1 depolarization injury. In addition, these data suggest that the use of agents that modulate the mito-KATP channel may provide a useful strategy in the prevention of brain injury from status epilepticus. Funding supported by: VA Research Service