Prostanoid Modulation of Neuronal Death

描述(申请人提供)：阿尔茨海默病和中风是老龄化人口中的常见疾病。每一种情况都以神经元死亡为特征，而可能防止这种情况的药物是非常重要的。一种非常有希望的预防神经元死亡的方法是使用环氧合酶(COX-2)的诱导型抑制剂，称为非类固醇抗炎药(NSAIDs)。然而，环氧合酶-2如何导致神经元死亡的机制尚不清楚。这项建议将使用体外神经元培养系统来研究COX-2衍生的代谢物PG-E2与由特定激动剂NMDA激活的谷氨酸受体介导的神经元死亡之间的相互作用。我们将研究PG-E2如何通过EP1或EP3前列腺素受体作用于神经元死亡。潜在的假设是，抑制COX-2产生的前列腺素PG-E2可通过阻止导致神经元死亡的EP1受体的激活来促进神经元在兴奋性毒性攻击中的存活。使用体外神经元培养系统将解决的关键问题是：1)其他PG-E受体药物是否如它们与EPI相互作用所预测的那样调节神经元死亡？2)PG-E受体(EP-1)的表达模式可能与神经元死亡有关？3)PG-E2通过星形胶质细胞等非神经细胞介导对神经元死亡(或存活)的贡献？4)PG-E与PG-E之间的相互作用对PG-E2的神经保护和神经破坏特性有何贡献？5)PG-E2对神经元基因表达谱有何影响？这项研究的具体目标是：具体目标1.研究混合神经元培养中的哪些PG受体参与PC-E2的神经破坏(通过拮抗NSAID介导的神经保护)与神经保护(在没有NSAID的情况下)的作用。具体目的#2.研究非神经元细胞在PG介导的神经元死亡中的作用。长期目标是这些研究将发现代谢途径中COX下游的新靶点(如PG-E受体)，以开发可应用于治疗神经退行性疾病的更安全、更有效的神经保护策略。

DESCRIPTION (provided by applicant): Alzheimer's disease and stroke are common conditions in the aging population. Each of these conditions is characterized by neuronal death, and agents that might prevent this are of great importance. One highly promising approach in preventing neuronal death is through the use of inhibitors of the inducible form of the enzyme cyclooxygenase (COX-2), termed Non Steroidal Anti-Inflammatory Drugs (NSAIDs). However, the mechanism of how COX-2 contributes to neuronal death is not known. This proposal will use an in vitro neuronal culture system to examine the interactions between the COX-2 derived metabolite PG-E2 and neuronal death mediated by glutamate receptors activated by the specific agonist NMDA. We will examine how PG-E2 acting through either the EP1 or EP3 prostanoid receptors contributes to neuronal death. The underlying hypothesis is that inhibition of the COX-2-generated prostanoid PG-E2 promotes neuronal survival during excitotoxic challenge by preventing activation of the EP1 receptor that contributes to neuronal death. The key questions which will be addressed in this proposal using an in vitro neuronal culture system are: 1) Do other PG-E receptor drugs modulate neuronal death as would be predicted by their interactions with EPI? 2) What is the expression pattern of the PG-E receptors (EP-1) as they may relate to neuronal death? 3) Is the contribution to neuronal death (or survival) by PG-E2 mediated through non-neuronal cells such as astrocytes? 4) What interactions between COX and PG-E2 contribute to the neuroprotective versus neurodestructive properties of PG-E2? 5) What is the influence by PG-E2 on the neuronal gene expression profile? The specific objectives for this study are:Specific Aim #1. To examine which PG receptors in mixed neuronal cultures contribute to theneurodestructive (by antagonism of NSAID-mediated neuroprotection) verses neuroprotective (in theabsence of NSAID) actions of PC-E2. Specific Aim #2. To examine contribution of non-neuronal cells towards neuronal death mediated by PG's. It is the long-term goal that these studies will identify new targets downstream from COX in the metabolic pathway (such as the PG-E receptors) to develop safer and more effective strategies of neuroprotection that could be applied to treating neurodegenerative diseases.