Neuronal cell death and gliosis are prominent features of many neurological disorders and degenerative diseases. In the rodent kainic acid (KA) model of temporal lobe epilepsy, a single systemic injection of KA produces prolonged and sustained seizures that cause the initial loss of many hippocampal pyramidal cells. Subsequently, a cascade of inflammatory events occurs including microglia activation, astrogliosis, and the additional loss of hippocampal neurons. There is considerable evidence that cyclo-oxygenase (COX) and lipoxygenase (LOX) participate in the neuronal cell loss that follows KA-induced seizure activity. In contrast to previous studies that have centered on KA-induced excitotoxic cell death and its prevention, this proposal will focus on the KA-induced neurodegeneration that results from reactive gliosis. These studies are significant because while the primary neuronal cell death resulting from injury may not be avoidable, the secondary loss potentially may be prevented.
The specific aims of this proposal are 1) to define the time course of reactive gliosis and neurodegeneration in the rat hippocampus following KA-induced seizure activity by immunohistochemical methods, 2) to examine the expression of COX and LOX in the hippocampus prior to and throughout the phase of reactive gliosis, and 3) to determine the contribution of COX and LOX to gliosis-associated neurodegeneration following prolonged seizure activity by pharmacological intervention and the use of transgenic knockout animals. These studies will provide insight into the events underlying gliosis-associated neuronal cell death and may be useful in developing therapeutic interventions for neuronal injury resulting from seizures, stroke, or other neurodegenerative diseases.
