Reactive nitrogen species as therapeutic targets for autophagy/mitophagy modulation to relieve neurodegeneration in multiple sclerosis: Potential application for drug discovery.

Multiple sclerosis (MS) is a neuroinflammatory disease with limited therapeutic effects, eventually developing into handicap. Seeking novel therapeutic strategies for MS is timely important. Active autophagy/mitophagy could mediate neurodegeneration, while its roles in MS remain controversial. To elucidate the exact roles of autophagy/mitophagy and reveal its in-depth regulatory mechanisms, we conduct a systematic literature study and analyze the factors that might be responsible for divergent results obtained. The dynamic change levels of autophagy/mitophagy appear to be a determining factor for final neuron fate during MS pathology. Excessive neuronal autophagy/mitophagy contributes to neurodegeneration after disease onset at the active MS phase. Reactive nitrogen species (RNS) serve as key regulators for redox-related modifications and participate in autophagy/mitophagy modulation in MS. Nitric oxide (NO) and peroxynitrite (ONOO), two representative RNS, could nitrate or nitrosate Drp1/parkin/PINK1 pathway, activating excessive mitophagy and aggravating neuronal injury. Targeting RNS-mediated excessive autophagy/mitophagy could be a promising strategy for developing novel anti-MS drugs. In this review, we highlight the important roles of RNS-mediated autophagy/mitophagy in neuronal injury and review the potential therapeutic compounds with the bioactivities of inhibiting RNS-mediated autophagy/mitophagy activation and attenuating MS progression. Overall, we conclude that reactive nitrogen species could be promising therapeutic targets to regulate autophagy/mitophagy for multiple sclerosis treatment.