Mitochondrial Inhibitor Models of Huntington’s Disease and Parkinson’s Disease Induce Zinc Accumulation and Are Attenuated by Inhibition of Zinc Neurotoxicity in vitro or in vivo

<b><i>Background:</i></b> Inhibition of mitochondrial function occurs in many neurodegenerative diseases, and inhibitors of mitochondrial complexes I and II are used to model them. The complex II inhibitor, 3-nitroproprionic acid (3-NPA), kills the striatal neurons susceptible in Huntington’s disease. The complex I inhibitor N-methyl-4-phenylpyridium (MPP⁺) and 6-hydroxydopamine (6-OHDA) are used to model Parkinson’s disease. Zinc (Zn²⁺⁾ accumulates after 3-NPA, 6-OHDA and MPP⁺ in situ or in vivo. <b><i>Objective:</i></b> We will investigate the role of Zn²⁺ neurotoxicity in 3-NPA, 6-OHDA and MPP⁺. <b><i>Methods:</i></b> Murine striatal/midbrain tyrosine hydroxylase positive, or near-pure cortical neuronal cultures, or animals were exposed to 3-NPA or MPP⁺ and 6-OHDA with or without neuroprotective compounds. Intracellular zinc ([Zn²⁺]_i), nicotinamide adenine dinucleotide (NAD⁺), NADH, glycolytic intermediates and neurotoxicity were measured. <b><i>Results:</i></b> We showed that compounds or genetics which restore NAD⁺ and attenuate Zn²⁺ neurotoxicity (pyruvate, nicotinamide, NAD⁺, increased NAD⁺ synthesis, sirtuin inhibition or Zn²⁺ chelation) attenuated the neuronal death induced by these toxins. The increase in [Zn²⁺]_i preceded a reduction in the NAD⁺/NADH ratio that caused a reversible glycolytic inhibition. Pyruvate, nicotinamide and NAD⁺ reversed the reductions in the NAD⁺/NADH ratio, glycolysis and neuronal death after challenge with 3-NPA, 6-OHDA or MPP⁺, as was previously shown for exogenous Zn²⁺. To test efficacy in vivo, we injected 3-NPA into the striatum of rats and systemically into mice, with or without pyruvate. We observed early striatal Zn²⁺ fluorescence, and pyruvate significantly attenuated the 3-NPA-induced lesion and restored behavioral scores. <b><i>Conclusions:</i></b> Together, these studies suggest that Zn²⁺ accumulation caused by MPP⁺ and 3-NPA is a novel preventable mechanism of the resultant neurotoxicity.