Efficacy of Erythropoietin (EPO) and EPO Analogues in the Treatment of Epilepsy

描述(由申请人提供)：很大比例的颞叶癫痫(TLE)患者对目前可用的药物没有反应，并在疾病过程中对大脑造成损伤。本申请旨在确定促红细胞生成素(EPO)作为治疗药物治疗TLE的疗效。重组人促红细胞生成素(RhEPO)是FDA批准的治疗贫血的药物，有很好的安全性记录。促红细胞生成素还被证明在许多神经疾病中具有神经保护作用。这项建议将测试重组人促红细胞生成素(高剂量可能有促红细胞生成素的副作用)和几种促红细胞生成素类似物-氨基甲酰化促红细胞生成素、去唾液促红细胞生成素和APA290(一种具有促红细胞生成素样特性的组织保护分子)在抑制匹罗卡品诱导的大鼠癫痫发作和神经保护方面的有效性(所有这些药物都没有促红细胞生成作用)。主要目的是确定能够改善癫痫发作并在不产生红血球作用的剂量下提供神经保护的最佳分子。在治疗过程中将进行NAA光谱成像，以确定一种非侵入性方法，在未来的人类转译研究中跟踪这些药物的有效性。如果被证明有效，这些分子未来可以用于治疗TLE甚至其他癫痫障碍的临床前和临床试验。 公共卫生相关性：本研究旨在探讨重组人促红细胞生成素及其类似物在匹罗卡品诱导的大鼠癫痫发作中减少或消除癫痫发作的效果。这是对翻译为人所用的一种探索性研究。

DESCRIPTION (provided by applicant): A large proportion of patients with temporal lobe epilepsy (TLE) does not respond to currently available medications, and in the course of the disease develop injury to the brain. This application proposes to determine the efficacy of erythropoietin (EPO) as a therapeutic agent in treating TLE. Recombinant human erythropoietin (rhEPO) is an already FDA approved drug for the treatment of anemia, which has a well-documented safety record. Erythropoietin has also been demonstrated to have neuroprotective effects in a number of neurological conditions. This proposal will test the efficacy of rhEPO (which in high doses may have erythropoietic side-effects) and several erythropoietic analogues - carbamylated erythropoietin, asialoerythropoietin, and APA290 a tissue protective molecule with EPO like properties (all of which do not have an erythropoietic effect) on the suppression of seizures and neuroprotection in a pilocarpine-induced seizure model in rats. The principal aim is to identify the best molecule that can ameliorate seizures and give neuroprotection at doses that do not have erythropoietic effects. NAA spectroscopic imaging during the course of treatment will be carried out to determine a non-invasive method for following the effectiveness of these drugs in intended future translational studies in humans. If proven efficacious, these molecules can in future be taken to preclinical and clinical trials for treatment of TLE and even other seizure disorders. Public Health Relevance: This study with explore the efficacy of recombinant human erythropoietin and new erythropoietin analogues which have neuroprotective but not erythropoietic effects in reducing or eliminating seizures in the pilocarpine induced seizures in rats. It is an exploratory study towards translation to human use.