This project examined neuronal and glial cells and interaction/signalling between these cells in nervous system injury. Within the nervous system cytokines are thought to have an active role in the pathophysiology of various neurological diseases and trauma. Early responses to chemical injury suggest a possible involvement of pro-inflammatory cytokines in the signalling process to initiate an injury response cascade of microglia activation, astrogliosis, neuronal necrosis and loss. We have demonstrated a spatio-temporal pattern of response for pro-inflammatory cytokines in chemical-induced injury of the mouse hippocampus. Glial cell cultures displayed a similar pattern of response to TMT both in morphology and cytokine production and can be modulated by the addition of a TNFalpha, IL-1alpha, and IL-6 antibody coctail. Co-cultures of glia and hippocampal neurons suggest a modulatory role for cytokines in that TNFalpha and IL-1alpha are shown to be necessary but not sufficient to produce neuronal degeneration. In vivo, pharmacological intervention of general anti-inflammatory agents has not been successful in preventing either the cytokine response of the neuronal degeneration. A specific pattern of neuronal and glia responses are elicited with antibodies to pro-inflammatory cytokines suggesting a more complicated multi-faceted process involved in chemical-induced neurodegeneration. The role of microglia proliferation was examined in the op/op genetic mouse mutant. In these mice, the inhibition of CSF-1 (a growth factor produced by astrocytes and a mitogenic agent for microglia) accelerated the damage induced by TMT but did not alter the pattern of neuronal degeneration.Future Research is based upon the hypothesis that cytokine/chemokine mediated responses and the interaction between neurons and glia play a critical role in neurodegeneration induced by disease processes, trauma, and environmental agents. Efforts will address the question if the microglia response and associated cytokine or toxic product formation and release are citical for astrocyte reacitivity and neurodegeneration. - mouse, brains, hippocampus, cytokines, neuroimmune RNase Protection Assay, neurotoxicology
