Harry GJ.
Cellular indicators of neuronal insult, Crisp Data Base National Institutes Of Health.
Abstract
Summary of Work: 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. The induction of mRNA for TNFa and interleukins shows a
differential response with regard to type of chemical-induced injury, in that patterns are different for a toxicant (trimethyltin) that produces
neuronal degeneration over a period of 10 days in the rat versus a rapid neuronal necrosis within 2 days in the mouse. Both have a different
pattern when compared to a chemical that targets the myelin sheath (triethyltin). In situ hybridization demonstrated the cellular localization of
TNFa, IL-1a in microglia while the protective cytokine TGF-b is localized in the surviving neurons suggesting a role for TGFb in
determining the differential sensitivity of neurons to injury. In vitro glia cultures displayed a similar pattern of response to TMT both in
morphology and cytokine production to TMT and can be modulated by the addition of a TNFa, IL-1a, IL-6 antibody cocktail or serine
protease inhibitors. Co-cultures of glia and hippocampal neurons suggest a modulatory role for cytokines in that TNFa and IL-1a are
shown to be necessary but not sufficient to produce neuronal degeneration. In vivo pharmacological intervention of anti-inflammatory agents
has not been successful in preventing either the cytokine response or the neuronal degeneration suggesting a more complicated multi-facted
process involved in chemical-induced neurodegeneration. Future Research: Research will address if the microglia response and associated
cytokine or toxic product formation and release are critical for astrocyte reactivity and neurodegeneration. This will be conducted with the
use of both pharmacological interventions, (cytokine antibodies, protease inhibitors, free radical scavangers) and specific transgenic mouse
models such as the bcl2 underexpressor, COX1 & COX2 knockout, and the op/op genetic mouse mutant each involved in the process of
neuronal apoptosis, astrocyte second messenger system, or peripheral macrophages and astrocyte colony stimulating factor, respectively.
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