title: 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.
abstract: BACKGROUND
  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 (Zn(2+)) accumulates after 3-NPA, 6-OHDA and MPP(+) in situ or in vivo.
  
  
  OBJECTIVE
  We will investigate the role of Zn(2+) neurotoxicity in 3-NPA, 6-OHDA and MPP(+).
  
  
  METHODS
  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 ([Zn(2+)](i)), nicotinamide adenine dinucleotide (NAD(+)), NADH, glycolytic intermediates and neurotoxicity were measured.
  
  
  RESULTS
  We showed that compounds or genetics which restore NAD(+) and attenuate Zn(2+) neurotoxicity (pyruvate, nicotinamide, NAD(+), increased NAD(+) synthesis, sirtuin inhibition or Zn(2+) chelation) attenuated the neuronal death induced by these toxins. The increase in [Zn(2+)](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 Zn(2+). 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 Zn(2+) fluorescence, and pyruvate significantly attenuated the 3-NPA-induced lesion and restored behavioral scores.
  
  
  CONCLUSIONS
  Together, these studies suggest that Zn(2+) accumulation caused by MPP(+) and 3-NPA is a novel preventable mechanism of the resultant neurotoxicity.
authors.affiliation: Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. csheli @ lsuhsc.edu
authors.forename: Christian T
authors.initials: CT
authors.lastname: Sheline
authors.forename: Julia
authors.initials: J
authors.lastname: Zhu
authors.forename: Wendy
authors.initials: W
authors.lastname: Zhang
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Shi
authors.forename: Ai-Li
authors.initials: AL
authors.lastname: Cai
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004099:Dihydroxyacetone Phosphate / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D004622:Embryo, Mammalian; D006597:Fructose-Bisphosphatase / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053513:Matrix Metalloproteinase 16 / Q000172:deficiency; D008565:Membrane Proteins / Q000172:deficiency; D026901:Membrane Transport Proteins; D001523:Mental Disorders / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009243:NAD / Q000378:metabolism / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects; D009536:Niacinamide / Q000627:therapeutic use; D009574:Nitro Compounds / Q000633:toxicity; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011422:Propionates / Q000633:toxicity; D019289:Pyruvic Acid / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009574:Nitro Compounds; D011422:Propionates; C491177:Slc30a3 protein, mouse; D009243:NAD; D009536:Niacinamide; D004099:Dihydroxyacetone Phosphate; D019289:Pyruvic Acid; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D006597:Fructose-Bisphosphatase; D053513:Matrix Metalloproteinase 16; D015032:Zinc; C015392:3-nitropropionic acid