CNS demyelination and oligodendrocyte death may be important function-limiting sequelae of many acute neurologic disorders including white matter stroke, global ischemia, brain and spinal cord trauma, and neonatal periventricular leukomalacia. However, cellular mechanisms leading to ischemic oligodendrocyte injury have only recently been explored. Toxic glutamate receptor activation contributes to hypoxic-ischemic neuronal injury, and while oligodendrocytes also express glutamate receptors, it is not known whether similar mechanisms can lead to oligodendrocyte death. This proposal examines the novel hypothesis that oligodendrocytes are vulnerable to excitotoxicity mediated by AMPA receptor overactivation, and that this vulnerability contributes to brain injury during cerebral ischemia. The investigators have studied injury in glial cell cultures from mouse cerebral hemispheres, consisting of oligodendrocytes maintained on an astrocyte monolayer to promote oligodendrocyte survival and differentiation. In this model, differentiated oligodendrocytes express AMPA receptors functionally coupled to calcium entry, and are selectively killed by exposure to low micromolar concentrations of selective AMPA receptor agonists. It is proposed to use cell culture and in vivo models to examine AMPA receptor-mediated ischemic oligodendrocyte dell death. The proposed research will determine the receptor pharmacology of oligodendrocyte excitotoxicity, examine cellular mechanisms of injury, and assess effects of agents predicted to attenuate oligodendrocyte death. Finally, the studies will assess the contribution of AMPA toxicity in hypoxic-ischemic injury of oligodendrocytes in cell culture and in mouse stroke models. The goal of these studies is to identify pharmacological approaches to reduction of white matter injury during stroke and other disorders characterized by oligodendrocyte loss.
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