Leptin As A Novel Neurohormonal Anticonvulsant

描述（由申请人提供）：癫痫折磨着250万美国人，并与显著的发病率和死亡率相关，特别是那些医学上难治性癫痫发作。过高的死亡率表现在预期寿命可能比正常寿命短10年。预期寿命较短的一个原因是癫痫持续状态，即一次长时间发作或一系列反复发作。幼儿和老年人的癫痫持续状态死亡率为20%。此外，癫痫每年给美国造成125亿美元的损失，其中至少一半用于25%的难治性癫痫患者。这些数据强调需要更好的癫痫和癫痫持续状态治疗方案。神经激素瘦素可能为解决这一需求提供一种新的方法。虽然瘦素以其调节体重的作用而闻名，但最近的证据表明，它是海马体中神经元兴奋性的有效调节剂。瘦素可以通过调节谷氨酸受体和钙活化钾通道来改变神经元的兴奋性。这一建议将测试瘦素具有抗惊厥特性的一般假设，这是由于其受体的激活。本研究旨在建立小鼠局灶性严重新皮质癫痫发作的体内模型：1)在局灶性新皮质癫痫发作的4-AP模型中，确定瘦素受体是否介导瘦素的抗惊厥作用；2)在局灶性新皮质癫痫4-AP体内模型中，明确瘦素抗惊厥作用的信号通路；3)在局灶性新皮质癫痫的体内4-AP模型中，确定鼻内给药瘦素是否具有抗惊厥作用。

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.