7. Conclusion
The etiology of PD remains unknown, and the mechanisms controlling the selective and progressive degeneration of the nigrostriatal dopaminergic pathway are poorly understood. Therapeutic intervention aimed at halting the degenerative nature observed in PD is of prime importance and presents some research opportunities. Studies of postmortem PD brains and various cellular and animal models of PD in the last two decades strongly suggest that the neuroinflammation caused by oxidative stress is one of the major mechanisms in PD pathology. It is believed that activated glial cells, which comprise the majority of this inflammatory response, contribute to neurodegeneration through the production of ROS. Currently, ROS-generating oxidative enzymes are emerging as major therapeutic targets to inhibit neurotoxicity seen in PD.
A range of data during the past few years suggest that anti-inflammatory agents with neuroprotective effects by inhibiting inflammatory oxidative enzymes in experimental models may be capable of preventing or reducing neuronal degeneration and arrest the progression of PD. Although several anti-inflammatory agents were known to inhibit the ROS, none has been specific and the results achieved are somewhat inconsistent and show limited mechanistic relevance to PD. Thus, inhibitors of major ROS-generating NADPH oxidase and iNOS that have a decent proven record of safety and efficacy would be promising candidates. The compounds discussed in this paper provide valuable information in selectively inhibiting the ROS generated by oxidative enzymes in in vitro and in vivo experimental models of PD. These compounds must be proved for their safety, selectivity, toxicity, bioavailability, therapeutic window, and absence of significant side effects. Furthermore, combination therapy of selected agents in the correct time frame and dose may also provide better results to achieve synergistic clinical effects.
However, a complete understanding of the molecular mechanisms of the specificities of ROS in PD, and larger studies both epidemiologic and randomized clinical trials in humans, as well as animal studies, are needed to validate these findings in delivering beneficial effects in the treatment of PD.