This project examined functional changes in neuronal and glial cells and the subsequent interaction and signalling between these cells in the nervous system following perturbation. Although various responses of neural cells exist, this work has focused on the response of microglia and astrocytes to neural injury and the role for pro-inflammatory cytokines, tumor necrosis factor and interleukins, as signalling mechanisms in the case of neurotoxicity. We have identified a temporal pattern of pro-inflammatory cytokine responses due to resident neural cells during chemically induced neurodegeneration. Using the prototypic neurotoxicant, trimethyltin (TMT) we have demonstrated an early and prolonged inflammatory response of the resident brain cells, microglia, with increased levels of mRNA for TNFa, and IL-1a. This is associated with an early and prolonged activation of transcription factors. A similar response pattern has been demonstrated in primary cultures of glial cells and in co-cultures of glial cells and hippocampal neurons. We have been able to modulate the glia response by anti-inflammatory agents and protease inhibitors. In the mouse, we have shown that TMT elevates mRNA for the pro-inflammatory cytokines, interferon gamma, chemokines and down-regulating cytokines in a time dependent manner. Specific patterns of cytokine responses are generated dependent upon the target site of the chemical, for example, exposure to triethyltin, a demyelinating agent, produces a more delayed onset of cytokine response with less involvement of the full pro-inflammatory cytokine network. Early responses to chemical injury suggest a possible involvement of pro- inflammatory cytokines i the signalling process to initiate the injury response cascade of neuronal necrosis, astrogliosis, and subsequent neuronal loss. The interaction between neurons and glia will be investigated by examining the signalling mechanism of cytokines on neuronal cells with regard to calcium homeostasis and gap-junctional communication. Our future research focuses on the activation of microglia which produces an early signalling event that may play a major role in subsequent neurodegeneration. Research will address the question of if the microglia response and associated product formation and release are critical to subsequent astrocyte reactivity and neurodegeneration and what factors are responsible for the down-regulation of the cytokine response in the brain.
