Abstract
Mitochondria play 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 Food and Drug Administration (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 reactive oxygen species (ROS). Similarly, addition of NTZ to cells pretreated with MPP+ could reverse block in mitochondrial OCR and reactive oxygen species induced by MPP+ in real time. 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 tyrosine hydroxylase (TH)-positive neurons of substantia nigra. Based on the above observations we believe that repurposing of NTZ for PD may offer therapeutic benefit.
Highlights
Parkinson’s disease (PD)3 is one of the most common neurodegenerative disorders that is characterized primarily by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNPc) leading to dopamine deficit in the striatum
The pathogenesis of PD appears to be converging on common pathways, such as mitochondrial dysfunction followed by oxidative stress and protein aggregation, which leads to apoptosis [9, 10]
We have investigated the efficacy of NTZ in dopaminergic cell lines against MPPϩ-induced alterations in the mitochondrial bioenergetics as well as in an acute MPTP mouse model of PD in both preventive and therapeutic models
Summary
Addition of rotenone (1.5 M) almost completely inhibited the OCR in control as well as NTZ-treated cells to similar extents, indicating that NTZ-induced OCR is derived from mitochondrial respiration (Fig. 2A). The observed effects of NTZ were found to be reversible as cells treated with NTZ (1 M in assay medium) for 1 h exhibited a significant increase in basal respiration and proton leak with a concomitant decrease in ATP production (Fig. 4, A and B). Addition of NTZ (1 and 5 M) to MPPϩ-treated cells immediately reversed the block in mitochondrial respiration at both the concentrations examined, and the values were found to be substantially higher than control cells (Fig. 5A). Mice treated with NTZ alone exhibited motor activity similar to that of control group (Fig. 7F)
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