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.
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