| The enteric nervous system (ENS) is the intrinsic nervous system of the gastrointestinal (GI) tract. Damage and degeneration of the ENS is a feature of some GI diseases, such as inflammatory bowel disease (IBD), and is associated with several other diseases including diabetes mellitis and Parkinson's disease. The overall goal of this thesis research was to identify specific classes of compounds capable of inducing ENS degeneration. These studies are intended to form a knowledge base upon which further studies can build towards the goal of preventing or attenuating clinical ENS damage.; Reactive oxygen species (ROS), proinflammatory cytokines, and the process of anoxia-reoxygenation have been identified as inducers of CNS neurodegeneration and mediators in the neuropathogenesis of inflammatory diseases. As the ENS bears a considerable functional resemblance to the CNS, these compounds and processes are likely to have similar actions in this nervous system. Many of these mediators have been implicated in the pathogenesis of inflammatory diseases of the bowel, whereas initial studies of some of these mediators suggest their involvement in ENS neuropathogenesis. Thus, the general hypothesis of this thesis is that anoxia-reoxygenation, ROS, and the proinflammatory cytokine tumor necrosis factor-α (TNF) act on the ENS to induce neurodegeneration.; In summary, the findings of this thesis are consistent with the hypothesis that inflammatory mediators can induce enteric neurodegeneration. This study identified specific inflammatory mediators as inducers of enteric neurodegeneration, characterized their neurodegenerative properties, and identified GDNF as a neuroprotective agent. Subsequent investigations further defined the respective roles of inflammatory immunocytes and the pro-inflammatory cytokine TNF in enteric neuronal cell death relevant to IBD pathogenesis. These findings are intended to form a basis for further studies into the mechanisms underlying clinical enteric neurodegeneration in disease pathogenesis. (Abstract shortened by UMI.)... |
