Roles of microglia and prostaglandin receptors in neuroprotection

Va Salt Lake City Healthcare System, Salt Lake City UT

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Abstract

DESCRIPTION (provided by applicant): There is an urgent need in the VA health care system for neuroprotective therapies that can be applied to promote neuronal survival following traumatic brain injury, stroke and neurodegenerative disease. A potential area for mitigating neuronal loss centers on regulating elements of neuroinflammatory processes associated with neuronal injury. A promising target that has been shown to play a major role in neuroinflammation and neuronal loss is the enzyme cyclooxygenase 2 (COX-2) which catalyzes the rate- limiting step in the synthesis of prostanoids. In animal models of stroke, increased neuronal survival is seen when the activity of this enzyme is diminished by either pharmacological or genetic manipulation. However, neuroprotective therapies utilizing COX-2 inhibitors are problematic because of cardiovascular complications associated with the use of these drugs. As such, recent efforts have begun to identify targets down stream of COX-2 such as the prostanoid receptors. The best example of this is seen with the EP1 receptor for prostaglandin E2 (PGE2) which has been shown to contribute to neuronal injury following excitotoxicity. Antagonists of EP1 increase neuronal survival in stroke models and in vitro in culture models following excitotoxic assault. Other inflammatory processes can also affect neuronal viability. Following injury in the central nervous system (CNS), inflammatory cells such as microglia migrate to the injured area and can render neurons more resistant to excitotoxic insults. However, little is known about how microglia interact with neurons to modulate neuronal viability through the EP1prostanoid receptor. We recently discovered that the neuroprotective effect of EP1 antagonists is lost when microglia are present. This finding indicates that the contribution to neuronal viability by neuronal EP1 can be regulated by microglia and has important implications in vivo where microglia are associated with neuronal injury. Based on our findings, we hypothesize that the neuroprotective properties conferred by microglia are achieved by altering EP1 and EP4 receptors in neurons. We have developed a powerful in vitro system which enables us to test this novel interaction between microglia and an important signaling pathway involved in neuronal viability. This proposal will test the hypothesis and may identify new neuroprotective strategies centered on microglial responses and modulation of EP receptors. SPECIFIC OBJECTIVES: Specific Aim #1: Determine if microglia mediate neuroprotection through attenuation of neuronal EP1. Specific Aim #2: Identify the soluble signals from microglia that alter EP1 response in neurons and increase neuronal resistance to NMDA. Specific Aim #3: Determine if microglial-induced loss of neuronal nuclear EP1 receptor expression contributes to increased neuronal survival. Specific Aim #4: Determine how the degree of microglial activation contributes to neuronal viability through modulation of neuronal EP1.