Convulsive status epilepticus is a prolonged self sustaining seizure which results in high morbidity and mortality. Current treatment of status epilepticus rests primarily on drugs that activate GABM receptors. GABAergic drugs are only effective in initiation phase of status epilepticus and lose effectiveness in sustained status epilepticus. When these drugs and phenytoin fail status epilepticus is treated with prolonged general anesthesia which is associated with high morbidity and mortality. A new class of drugs is necessary for the treatment of sustained status epilepticus. Preliminary studies find that NMDA receptor antagonists are effective in terminating sustained status epilepticus. Further, there is a potential mechanism of NMDA receptor activation during status epilepticus. NMDA receptors are only partially activated during normal low frequency excitatory synaptic activity in the hippocampus due to magnesium block of the receptor. This block can however be relieved by membrane depolarization. Compared to CA1 pyramidal neurons acutely isolated from control animals, the CA1 pyramidal neurons from animals in sustained status epilepticus have a markedly depolarized membrane potential. This depolarization is likely to remove Mg2+ block of NMDA receptors allow their activation. The proposal seeks to extend studies on NMDA receptor mechanisms in sustaining status epilepticus by testing two hypotheses. First, NMDA receptor antagonists are superior to conventional GABAergi c agents in terminating sustained (>60 minutes) status epilepticus and second there is increased activation of NMDA receptors on CA1 pyramidal neurons during sustained status epilepticus. The overall design of experiments seeks to combine insights from NMDA receptor antagonist treatment of experimental status epilepticus with patch clamp analysis of NMDA receptor currents in hippocampal CA1 pyramidal neurons acutely isolated from rats undergoing status epilepticus. This proposal tests hypotheses by fulfilling specific aims: 1) Comparing the efficacy of four classes of NMDA receptor antagonists with two GABAergic agents in controlling sustained status epilepticus and 2) Characterizing the resting membrane potential, NMDA and sensitivity, pH and redox sensitivity of NMDA receptors on CA1 neurons acutely isolated from hippocampi of rats undergoing sustained status epilepticus. These studies will provide animal data to design and execute human clinical trails for treatment of refractory status epilepticus with NMDA receptor antagonists. These studies will provide insights into mechanisms of NMDA receptor activation on vulnerable neurons during status epilepticus.
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