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 摘要摘要癫痫病与显着的死亡率和发病率有关，估计对美国的年成本为150亿美元。每年在美国诊断出约15万例新病例癫痫病。抗性药物的钝性药物癫痫患者的癫痫发作不会阻止癫痫的发展。创伤后癫痫（PTE）发生在患者中由于脑外伤（TBI）。穿透性TBI后成人癫痫的发生率约为50％。因此，是鉴定可与抗塞氏菌药物一起施用的新型辅助治疗剂非常重要延迟进展并防止PTE和其他类型的癫痫的发展。在TBI和癫痫发作后，在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，我们已经表明，限于前脑神经元的COX-2缺失对毛磷脂诱导的状态模型有益癫痫病（SE）。 PGE2受体EP2的选择性拮抗剂概括了条件COX-2删除的许多特征在SE模型中，通过弄伤几个促炎性介质，神经胶质变性和神经退行性，表明大多数 COX-2促炎作用是通过脑损伤模型中EP2受体介导的。因此，我们假设靶向COX-2下游EP2受体将是开发抗癫痫发作的优越策略治疗。在这项研究中，我们建议测试是否靶向用小分子靶向EP2受体拮抗剂将是大鼠鼻旁胶液搅拌损伤（RPFPI）模型的抗癫痫发作。癫痫。 OMB No. 0925-0001/0002（Rev. 08/12批准通过8/31/2015）页面延续格式页面