Leptin As A Novel Neurohormonal Anticonvulsant

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DESCRIPTION (provided by applicant): Epilepsy afflicts 2.5 million Americans and is associated with significant morbidity and mortality especially for those with medically refractory seizures. The excess mortality is manifest in a life expectancy that can be 10 years shorter than normal. One reason for the shorter life expectancy is status epilepticus, which is a single prolonged seizure or a series of repetitive seizures. Status epilepticus has a mortality rate of 20% in very young children and the elderly. Moreover, epilepsy costs the United States $12.5 billion per year of which at least half goes to the 25% of patients with medically intractable epilepsy. These data underscore the need for better treatment options for epilepsy and status epilepticus. The neurohormone leptin may provide a novel method for addressing this need. Although leptin is best known for its role in regulating body weight, recent evidence indicates that it is a potent and effective modulator of neuronal excitability in the hippocampus. Leptin can alter neuronal excitability by modulating glutamatergic receptors and calcium-activated potassium channels. This proposal will test the general hypothesis that leptin has anticonvulsant properties resulting from the activation of its receptor. The specific goals are to use an in vivo model of severe focal neocortical seizures induced by the proconvulsant 4-aminopyridine (4-AP) in rodents to: 1) Determine whether the leptin receptor mediates the anticonvulsant effect of leptin in the in vivo 4-AP model of focal neocortical seizures; 2) Identify the signaling pathway that mediates the anticonvulsant effect of leptin in the in vivo 4-AP model of focal neocortical seizures; 3) Determine whether intranasally administered leptin acts as an anticonvulsant in the in vivo 4-AP model of focal neocortical seizures.