The inflammatory response develops rapidly and robustly after spinal cord injury (SCI), promoting the spread of secondary injury and loss of tissue and function. Platelet-activating factor (PAF) is an inflammatory molecule found in central nervous system tissue and is toxic to neurons when present in elevated levels. Therefore, elevated PAF resulting from SCI could enhance neurotoxicity, either by direct actions on neurons or by affecting glial support cells such as astrocytes. This proposal will examine the potential mechanisms of PAF-induced neurotoxicity which might involve primary changes in astrocyte function. These questions are addressed in the following specific aims: 1) test the hypothesis that inhibition of glutamate uptake in astrocytes exposed to PAF is a receptor mediated event, 2) test the hypothesis that PAF acts to inhibit glutamate uptake via specific G-protein related signaling pathways, and 3) test the hypothesis that astrocyte cell death induced by PAF is apoptotic in nature. The proposed studies will be accomplished primarily in cell culture models, and results will lead to a greater understanding of inflammatory events involving PAF which might contribute to neurotoxicity and functional loss after SCI.
