title: The neuroprotection of hydrogen sulfide against MPTP-induced dopaminergic neuron degeneration involves uncoupling protein 2 rather than ATP-sensitive potassium channels.
abstract: OBJECTIVE
  Hydrogen sulfide (H(2)S), a novel gaseous mediator, has been recognized to protect neurons from overexcitation by enhancing the activity of the adenosine triphosphate-sensitive potassium (K-ATP) channel. However, no direct evidence supports that the K-ATP channel contributes to the neuroprotective effect of H(2)S in neurodegeneration. Herein, wild-type and Kir6.2 knockout (Kir6.2(-/-)) mice were used to establish the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD) so as to investigate the involvement of K-ATP channels in the neuroprotection of H(2)S.
  
  
  RESULTS
  Systemic administration of sodium hydrosulfide (NaHS) (an H(2)S donor, 5.6 mg/kg/day) for 7 days rescued MPTP-induced loss of dopaminergic (DA) neurons in substantia nigra compacta of both Kir6.2(+/+) and Kir6.2(-/-) mice. Consistently, NaHS (100 μM) protected primary mesencephalic neurons against 1-methyl-4-phenylpyridinium (MPP(+))-induced cytotoxicity in both genotypes. We further found that deficiency of mitochondrial uncoupling protein 2 (UCP2), which reduces reactive oxygen species (ROS) production and functions as upstream to the K-ATP channel in determining vulnerability of DA neurons, abolished the protective effects of H(2)S against either DA neuron degeneration in the PD mouse model or MPP(+)-induced injury in primary mesencephalic neurons. Rationally, UCP2 evokes mild uncoupling, which in turn diminishes ROS accumulation in DA neurons. Furthermore, H(2)S exerted neuroprotective effect via enhancing UCP2-mediated antioxidation and subsequently suppressing ROS-triggered endoplasmic reticulum stress as well as ultimately inhibiting caspase 12-induced neuronal apoptosis.
  
  
  CONCLUSIONS
  H(2)S protects DA neurons against degeneration in a UCP2 rather than Kir6.2/K-ATP channel-dependent mechanism, which will give us an insight into the potential of H(2)S in terms of opening up new therapeutic avenues for PD.
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Zhao
authors.forename: Juan-Juan
authors.initials: JJ
authors.lastname: Tang
authors.forename: Cun-Jin
authors.initials: CJ
authors.lastname: Su
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Ding
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Bian
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism*; D006836:Hydro-Lyases / Q000235:genetics / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D007150:Immunohistochemistry; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2; D000099161:Kcnj11 Channel
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006836:Hydro-Lyases; D006862:Hydrogen Sulfide; D007473:Ion Channels; D054086:KATP Channels; D024101:Mitochondrial Proteins; D024661:Potassium Channels, Inwardly Rectifying; D017382:Reactive Oxygen Species; D000071246:Uncoupling Protein 2; D000099161:Kcnj11 Channel; C000604390:Ucp2 protein, mouse; C045581:lactate dehydratase