AIMS :The major goal of this project was to examine the roles of the opioid systems in modulating the expression of inflammatory factors in microglia and in the mediation of immune-related neurodegeneration. We have employed both in vitro and in vivo rodent models of Parkinson's disease by focusing our studies on the mesencephalic dopaminergic neurons. Our laboratory was among the first to report that lipopolysaccharide (LPS)-induced neurotoxicity depended on the presence of glial cells. These cells secrete a variety of proinflammatory factors, including cytokines, free radicals and arachidonate metabolites that are the main contributors to the pathogenesis of inflammation-related neurodegenerative diseases. Our current efforts focus on determining the relative importance of these proinflammatory factors in glia-mediated neuronal damage.ACCOMPLISHMENTS :We have examined the effects of opioids on the activity of microglia and its relationship to inflammation-related neurodegenerative diseases. Among the different families of opioid peptides studied, the most important finding was the potent neuroprotective effects of ultralow concentrations (10-14-10-16 M) of dynorphins against LPS-induced damage to dopaminergic neurons. We observed these effects in both mixed mesencephalic neurons/glia cultures and animal models. Immunocytochemical analysis revealed that the reduction of LPS-induced activation of microglia by dynorphins was associated with their neuroprotective effects. Another intriguing finding from this series of studies was the observation that naloxone, an opioid receptor antagonist, exhibited the same neuroprotective efficacy as dynorphins, which are opioid receptor agonists. Pharmacological studies using different analogs of dynorphins and optical isomers of naloxone demonstrated that the inhibitory effects on microglial activity and the neuroprotective effect of both dynorphins and naloxone were not mediated through the classical opioid receptors. These results explained why both opioid agonists and antagonists exert similar effects. Moreover, our studies revealed important non-opioid actions of these two opioid compounds. Further studies are planned to elucidate the mechanism for both dynorphins- and naloxone-mediated inhibition of microglia activation and their mode of neuroprotective actions. Our studies should provide a new strategy in the search for novel neuroprotective agents of clinical benefit.
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