Leptin As A Novel Neurohormonal Anticonvulsant

描述（由申请人提供）：癫痫困扰着250万美国人，并且与显著的发病率和死亡率相关，特别是对于那些患有医学难治性癫痫发作的人。死亡率过高表现在预期寿命比正常情况短10年。预期寿命较短的一个原因是癫痫持续状态，这是一个单一的长期癫痫发作或一系列重复发作。癫痫持续状态在非常年幼的儿童和老年人中的死亡率为20%。此外，癫痫每年花费美国125亿美元，其中至少一半用于25%的患有医学难治性癫痫的患者。这些数据强调需要更好的治疗选择癫痫和癫痫持续状态。神经激素瘦素可能提供一种新的方法来满足这一需求。虽然瘦素最为人所知的是其在调节体重中的作用，但最近的证据表明，它是海马中神经元兴奋性的强有力且有效的调节剂。瘦素可通过调节多巴胺能受体和钙激活钾通道来改变神经元的兴奋性。这个建议将测试瘦素具有抗惊厥特性的一般假设，其受体的激活。本研究的具体目的是利用致惊厥剂4-氨基吡啶（4-aminopyridine，4-AP）诱导的啮齿类动物严重局灶性新皮层癫痫发作的体内模型，以：1）确定瘦素受体是否介导瘦素在局灶性新皮层癫痫发作的体内4-AP模型中的抗惊厥作用; 2）确定在局灶性新皮层癫痫发作的体内4-AP模型中介导瘦素抗惊厥作用的信号通路; 3）确定鼻内施用的瘦素是否在局灶性新皮质癫痫发作的体内4-AP模型中起抗惊厥剂的作用。

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.