Leptin As A Novel Neurohormonal Anticonvulsant

瘦素作为一种新型神经激素抗惊厥药

基本信息

批准号：
7356365
负责人：
KWEE LIU LIN THIO
金额：
$ 16.63万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7356365
关键词：
1-Phosphatidylinositol 3-Kinase 4-Aminopyridine Address Affect American Anticonvulsants Antiepileptic Agents Body Weight Brain Calcium Calcium-Activated Potassium Channel Calcium-Sensing Receptors Cessation of life Child Clinical Condition Data Depressed mood Development Elderly Epilepsy Excess Mortality Glutamates Goals Hippocampus (Brain)In Vitro Intractable Epilepsy Intranasal Administration Ion Channel Lead Leptin Life Life Expectancy Mediating Methods Modeling Morbidity - disease rate Motor Seizures Neurohormones Neurons Outcome Patients Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphotransferases Potassium Principal Investigator Property Propionic Acids Propionic acid Rate Rattus Refractory Research Risk Rodent Rodent Model Role Seizures Series Serum Signal Pathway Status Epilepticus Synapses Testing United States Work cost improved in vivo in vivo Model ketogenic diet large-conductance calcium-activated potassium channels leptin receptor mortality neocortical neuronal excitability novel programs receptor stem

项目摘要

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.

描述（由申请人提供）：癫痫症困扰着 250 万美国人，并且与显着的发病率和死亡率相关，特别是对于那些医学上难治性癫痫发作的患者。死亡率过高表现为预期寿命比正常水平短 10 年。预期寿命较短的一个原因是癫痫持续状态，这是一次长时间的癫痫发作或一系列重复性癫痫发作。癫痫持续状态在幼儿和老年人中的死亡率为 20%。此外，美国每年因癫痫花费 125 亿美元，其中至少一半花在 25% 的难治性癫痫患者身上。这些数据强调需要更好的癫痫和癫痫持续状态治疗选择。神经激素瘦素可能为满足这一需求提供一种新方法。尽管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激活钾通道来改变神经元兴奋性。该提案将检验瘦素因其受体激活而具有抗惊厥特性的一般假设。具体目标是使用促惊厥剂 4-氨基吡啶 (4-AP) 在啮齿类动物中诱导严重局灶性新皮质癫痫的体内模型来： 1) 确定瘦素受体是否介导体内 4-氨基吡啶 (4-AP) 的瘦素抗惊厥作用。局灶性新皮质癫痫AP模型； 2）确定局灶性新皮质癫痫体内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的体内 4-AP 模型中起到抗惊厥作用。