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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：
10026712
负责人：
Thota Ganesh
金额：
$ 38.93万
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：
2017-12-15 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10026712
关键词：
Acute Adult Aftercare Albumins Animal Model Animals Anti-Inflammatory Agents 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 Morbidity - disease rate Mus Neocortex Nerve Degeneration Neurons Oral PTGS2 gene Patients Pharmaceutical Preparations Pharmacology Study Phase Pilocarpine Plasma Plasma Enhancement Play Post-Traumatic Epilepsy Pre-Clinical Model Prevention therapy 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 blood-brain barrier permeabilization controlled release cost fluid percussion injury in vivo inflammatory marker intraperitoneal lead optimization mortality neuron loss neuropathology novel prevent receptor small molecule subcutaneous treatment effect

项目摘要

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.

癫痫与严重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。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacological antagonism of EP2 receptor does not modify basal cardiovascular and respiratory function, blood cell counts, and bone morphology in animal models.

DOI：
10.1016/j.biopha.2022.112646
发表时间：
2022-03
期刊：
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
影响因子：
0
作者：
Rawat V;Banik A;Amaradhi R;Rojas A;Taval S;Nagy T;Dingledine R;Ganesh T
通讯作者：
Ganesh T

Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties.

DOI：
10.1021/acs.molpharmaceut.8b00764
发表时间：
2018-12-03
期刊：
Molecular pharmaceutics
影响因子：
4.9
作者：
Ganesh T;Banik A;Dingledine R;Wang W;Amaradhi R
通讯作者：
Amaradhi R

Targeting EP2 Receptor for Drug Discovery: Strengths, Weaknesses, Opportunities, and Threats (SWOT) Analysis.

DOI：
10.1021/acs.jmedchem.3c00655
发表时间：
2023-07-27
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Ganesh, Thota
通讯作者：
Ganesh, Thota

Azaindole therapeutic agents.

DOI：
10.1016/j.bmc.2020.115830
发表时间：
2020-12-15
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Motati DR;Amaradhi R;Ganesh T
通讯作者：
Ganesh T

A Novel Second-Generation EP2 Receptor Antagonist Reduces Neuroinflammation and Gliosis After Status Epilepticus in Rats.

新型第二代 EP2 受体拮抗剂可减少大鼠癫痫持续状态后的神经炎症和神经胶质增生。

DOI：
10.1007/s13311-020-00969-5
发表时间：
2021
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
0
作者：
Rojas,Asheebo;Amaradhi,Radhika;Banik,Avijit;Jiang,Chunxiang;Abreu-Melon,JuanMartin;Wang,Sarah;Dingledine,Raymond;Ganesh,Thota
通讯作者：
Ganesh,Thota