The Unintended Mitochondrial Uncoupling Effects of the FDA Approved Anti-Helminth Drug Nitazoxanide Mitigates Experimental Parkinsonism in Mice [Bioenergetics]

Mitochondria plays a primary role in the pathophysiology of Parkinson's disease (PD) and small molecules that counteract the initial stages of disease may offer therapeutic benefit. In this regard, we have examined whether the off-target effects of the FDA approved anti-helminth drug, nitazoxanide (NTZ) on mitochondrial respiration could possess any therapeutic potential for PD. Results indicate that MPP+ induced loss in oxygen consumption rate (OCR) and ATP production by mitochondria were ameliorated by NTZ in real-time by virtue of its mild-uncoupling effect. Pretreatment of cells with NTZ mitigated MPP+ induced loss in mitochondrial OCR and ROS. Similarly, addition of NTZ to cells pre-treated with MPP+ could reverse block in mitochondrial OCR and ROS induced by MPP+ in realtime. The observed effects of NTZ were found to be transient and reversible as removal of NTZ from incubation medium restored the mitochondrial respiration to that of controls. Apoptosis induced by MPP+ was ameliorated by NTZ in a dose-dependent manner. In vivo results demonstrated that oral administration of NTZ (50 mg/kg) in an acute MPTP mouse model of PD conferred significant protection against the loss of TH positive neurons of Substantia nigra. Based on the above observations we believe that repurposing of NTZ for PD may offer therapeutic benefit.

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