TNF and Cell Death in the Rat Spinal Cord White Matter

Ohio State University, Columbus OH

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Abstract

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) is a serious ailment, seriously crippling those affected, and costing our nation some 20 billion dollars each year. The central nervous system (CNS) is not thought to repair itself after injury, but instead, it undergoes substantial secondary injury resulting in larger, more debilitating lesions. Tumor necrosis factor alpha (TNFa) and glutamate - both molecules released in high concentrations after SCI - appear to act synergistically in bringing about rapid cell death in spinal cord gray matter, as TNFa upregulates glutamate receptors on the neuronal cell surface. However, it is not yet known what effects, if any, the excitotoxic release of TNFa and glutamate has on the surrounding white matter, and what role these molecules play in the expanding lesion of secondary cell death. Oligodendrocytes (oligos) in the white matter are known to be particularly sensitive to secondary cell death after SCI, upregulating expression of the p75 "death" receptor. Thus, oligo reaction to TNFa and glutamate-agonists will be examined with the hypotheses that: 1) TNFa potentiates the excitotoxic effect of glutamate-agonists on oligos in vivo, 2) TNFa increases localization of glutamate receptors to the oligo cell surface, and 3) low doses of TNFa induce p75 expression, making olig0s more likely to undergo apoptosis.