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EP2 antagonists as novel anti-epileptogenic agents

EP2拮抗剂作为新型抗癫痫药物

基本信息

批准号：
9456366
负责人：
Thota Ganesh
金额：
$ 40.37万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9456366
关键词：
Acute Adult Aftercare Albumins Animal Model Animals Anti-inflammatory Antiepileptogenic Astrocytes Atrophic Behavioral Blood - brain barrier anatomy Brain Brain Injuries Chronic Craniocerebral Trauma Cytokine Activation Development Diagnosis Dinoprostone Dose Drug Kinetics Electrocorticogram Epilepsy Epileptogenesis Excipients Formulation Frequencies Functional disorder Future Generations Gliosis Goals Half-Life Hippocampus (Brain)Incidence Infiltration Inflammation Inflammatory Inflammatory Response Isoflurophate Leukocytes Measures Mediating Mediator of activation protein Microglia Modeling Mono-S Morbidity - disease rate Mus Neocortex Nerve Degeneration Neurons Oral PTGS2 gene Patients Permeability Pharmaceutical Preparations Pharmacology Study Phase Pilocarpine Plasma Plasma Enhancement Play Pre-Clinical Model Prevention therapy Principal Investigator Property Prosencephalon Prostaglandin E Receptor Prostaglandins Rattus Recurrence Risk Rodent Model Route Safety Seizures Status Epilepticus Synapses Testing Therapeutic Therapeutic Agents Time Tissues Traumatic Brain Injury United States controlled release cost fluid percussion injury in vivo inflammatory marker intraperitoneal lead optimization mortality neuron loss neuropathology novel prevent programs receptor small molecule subcutaneous treatment effect

项目摘要

Program Director/Principal Investigator (Last, First, Middle): Ganesh, Thota Lay summary Epilepsy is associated with significant mortality and morbidity, with an estimated annual cost of $15 billion to the USA. About 150,000 new cases of epilepsy are diagnosed in the United States each year. The anti-seizure drugs, which blunt seizures in epilepsy patients, do not prevent the development of epilepsy. Posttraumatic epilepsy (PTE) arises in patients due to traumatic brain injury (TBI). The incidence of epilepsy in adults after a penetrating TBI is about 50%. Thus, it is very important to identify novel adjunct therapeutic agents which can be administered along with anti-seizure drugs to delay the progression and prevent the development of PTE and other types of epilepsy. Induction of COX-2 and PGE2 were found in the brain of patients and rodent models after TBI and seizures. Recently, we have shown that COX-2 deletion restricted to forebrain neurons is beneficial in pilocaprine induced model of status epilepticus (SE). A selective antagonist of PGE2 receptor EP2 recapitulated many features of conditional COX-2 deletion in SE model by blunting several proinflammatory mediators, gliosis and neurodegeneration, suggesting that most of the COX-2 proinflammatory effects are mediated through EP2 receptor in a brain injury model. Thus, we hypothesized that targeting EP2 receptor, downstream of COX-2, will be a superior strategy for the development of anti-epileptogenic therapy. In this study, we propose to test a proof-of-concept whether targeting EP2 receptor with small molecule antagonist will be anti-epileptogenic in rat rostral parasagittal fluid percussion injury (rpFPI) model of posttraumatic epilepsy. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page

项目总监/首席研究员（最后、第一、中间）：Ganesh、Thota 外行总结癫痫与显着的死亡率和发病率相关，估计每年给美国造成 150 亿美元的损失。美国每年诊断出约 150,000 例新发癫痫病例。抗癫痫药物，可以减弱癫痫患者癫痫发作时，不能阻止癫痫的发展。患者出现创伤后癫痫（PTE）由于创伤性脑损伤（TBI）。成人穿透性 TBI 后癫痫的发病率约为 50%。因此，它是确定可以与抗癫痫药物一起服用的新型辅助治疗剂非常重要延缓 PTE 和其他类型癫痫的进展并预防其发展。在 TBI 和癫痫发作后的患者和啮齿动物模型的大脑中发现了 COX-2 和 PGE2 的诱导。最近，我们研究表明，仅限于前脑神经元的 COX-2 缺失在毛山羊碱诱导的状态模型中是有益的癫痫（SE）。 PGE2 受体 EP2 的选择性拮抗剂重现了条件性 COX-2 缺失的许多特征在 SE 模型中，通过削弱几种促炎介质、神经胶质增生和神经变性，表明大多数在脑损伤模型中，COX-2 促炎作用是通过 EP2 受体介导的。因此，我们假设靶向 COX-2 下游的 EP2 受体将是开发抗癫痫药物的优越策略治疗。在这项研究中，我们建议测试小分子是否能靶向 EP2 受体拮抗剂在创伤后大鼠头端旁矢状液冲击损伤（rpFPI）模型中具有抗癫痫作用癫痫。 OMB 编号 0925-0001/0002（修订版 08/12 已批准至 8/31/2015）页面延续格式页面