Neuroprotective Effect of Naloxone Stereoisomers on Dopaminergic Neurons in the Inflammation Related Model of PD

The establishment of both in vitro and in vivo inflammation-related models of PD has enabled the search for and study of the mechanism of action responsible for a variety of neuroprotective agents. Of particular interest is the neuroprotective effect of the naloxone stereoisomers. In the in vitro neuron-glia culture system, 1 ^M (-)-naloxone afforded significant protection of dopaminergic neurons against LPS-induced degeneration. Interestingly, (+)-naloxone, which lacks opioid receptor binding activity, was equally effective (69). The neuroprotective effect of naloxone was most likely unrelated to the opioid system because both compounds effectively inhibited the activation of microglia and their production of NO, TNF-a, and especially the superoxide free radical (69,82; Fig. 2). The in vitro observations were confirmed by in vivo studies where systemic administration of naloxone with an osmotic minipump reduced the loss of nigral dopaminergic neurons induced by LPS injection (67,68). Again, both (-)-naloxone and (+)-naloxone were equally effective (67). Interestingly, over the last several decades, several groups have described nonopioid effects of (+)-naloxone in various systems (71-74). In addition, Simpkins and associates have reported that both naloxone stereoisomers are capable of suppressing the chemoattractant-induced activation of human neutrophils (75,76). Therefore, it is possible that naloxone, regardless of its stereoconfigurations, is an effective modulator of immune cell activity. The appreciation of nonopioid and immune modulatory activity of naloxone and, at the same time, the increasing awareness of the role of inflammation in many disease conditions, may help redefine the mechanism of action for the observed efficacy of naloxone in the experimental treatment of a variety of pathological conditions. For example, whether the beneficial effects observed for naloxone in the treatment of spinal cord and traumatic brain injuries and myocardiac/ cerebral stroke are related to any potential inhibitory effect on the secondary inflammatory response occurred following the initial phase of cell death remains to be examined (17-19). Interestingly, in the experimental treatment of Alzheimer's disease, naloxone was found to be much more promising in younger patients (77,78) than in more advanced cases (79,80). It would be of great interest to determine whether these results imply that reduction by naloxone of the inflammatory response at an earlier stage of the progression of the disease will have a more favorable final outcome. Similarly, the beneficial effect of naloxone in the experimental treatment of bacterial sepsis may also be related to its negative modulatory effect on the immune cells, although it may be

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