Role of platelet-activating factor in spinal cord injury and in modulating glial cell function and viability

The biologically active lipid metabolite, platelet-activating factor (PAF), is a mediator of inflammatory processes in both peripheral tissues and the central nervous system (CNS). Within the CNS, PAF is capable of regulating normal physiological function. This is thought to occur when PAF levels are tightly controlled. However, PAF production increases upon injury or inflammation in the CNS and likely contributes to pathological processes and tissue damage. The present studies examined the involvement of PAF in secondary pathology after spinal cord injury. More detailed investigation focused on the ability of PAF to alter cell function and viability in cultured astrocytes, a principal glial cell in the CNS. Additional studies examined the effects of PAF on viability of oligodendrocytes, which are critical for normal neuronal function.; In vivo approaches were used to investigate the role of PAF after spinal cord injury. A PAF antagonist, WEB 2170, was administered for various timepoints after injury followed by tissue analysis for lesion size and tissue sparing. Subsequent in vivo studies used the RNase Protection Assay to establish the time course of pro-inflammatory cytokine induction following injury, as well as the effects of WEB 2170 treatment in decreasing cytokine mRNA levels. PAF-induced alterations in glial cell function or viability were assessed using CNS astrocytes and oligodendrocytes grown in vitro. It was first established that these cells possessed a PAF receptor. Cells were treated with increasing concentrations of PAF and a variety of effects investigated, including inhibition of glutamate uptake, cell death, and caspase-3 activation. The PAF antagonists, WEB 2170 and BN 52021, verified the specificity of PAF effects.; Results indicate that PAF contributes to acute secondary pathology after spinal cord injury and that one mechanism may involve induction of pro-inflammatory cytokines. PAF treatment inhibited glutamate uptake by astrocytes and lead to cell death in astrocytes and oligodendrocytes in vitro, an effect involving activation of the pro-apoptotic enzyme, caspase-3. The studies support the role of PAF as a mediator of secondary injury in the CNS and as a potential toxin to CNS glial cells.