Abstract
Reactive oxygen species (ROS) overproduction contributes to the neurotoxicity of 1-methy-4-phenylpyridinium ion (MPP+). Increasing studies have shown that hydrogen sulfide (H2S) is an endogenous antioxidant gas. We have hypothesized that MPP+-caused neurotoxicity may involve the imbalance of proportion to this endogenous protective antioxidant gas. The aim of this study is to evaluate whether MPP+ disturbs H2S synthesis in PC12 cells, a clonal rat pheochromocytoma cell line, and whether disturbance of H2S generation induced by MPP+ is an underlying mechanism of MPP+-induced neurotoxicity. We show that exposure of PC12 cells to MPP+ causes a significant decrease in H2S generation and results in remarkable cell damage. We find that cystathionine-β-synthetase (CBS) is catalyzed in PC12 cells to generate H2S, and that both expression and activity of CBS are inhibited by MPP+ treatment. Exposure of sodium hydrosulfide (NaHS), a donor of H2S, extenuates MPP+-induced cytotoxicity and ROS accumulation in PC12 cells, while inhibition of CBS by amino-oxyacetate (AOAA) exacerbates the effects of MPP+. These results indicate that MPP+ neurotoxicity involves reduction of H2S production, which is caused by inhibition of CBS. This study provides novel insights into cell death observed in neurodegenerative disease such as Parkinson’s disease.
Similar content being viewed by others
References
Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16:1066–1071
Abou-Sleiman PM, Muqit MM, Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 7:207–219
Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, Verna JM (2001) Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 65:135–172
Chang L, Geng B, Yu F, Zhao J, Jiang H, Du J, Tang C (2008) Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats. Amino Acids 34:573–585
Cheung NS, Peng ZF, Chen MJ, Moore PK, Whiteman M (2007) Hydrogen sulfide induced neuronal death occurs via glutamate receptor and is associated with calpain activation and lysosomal rupture in mouse primary cortical neurons. Neuropharmacology 53:505–514
Dawson TM, Dawson VL (2002) Neuroprotective and neurorestorative strategies for Parkinson’s disease. Nat Neurosci 5(Suppl):1058–1061
Dwyer BE, Raina AK, Perry G, Smith MA (2004) Homocysteine and Alzheimer’s disease: a modifiable risk? Free Radic Biol Med 36:1471–1475
Elrod JW, Calvert JW, Morrison J, Doeller JE, Kraus DW, Tao L et al (2007) Hydrogen sulfide attenuates myocardial ischemia–reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci USA 104:15560–15565
Geng B, Chang L, Pan C, Qi Y, Zhao J, Pang Y, Du J, Tang C (2004) Endogenous hydrogen sulfide regulation of myocardial injury induced by isoproterenol. Biochem Biophys Res Commun 318:756–763
Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci USA 73:2424–2428
Heikkila RE, Hess A, Duvoisin RC (1984) Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice. Science 224:1451–1453
Hosoki R, Matsuki N, Kimura H (1997) The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun 237:527–531
Hu LF, Lu M, Wu ZY, Wong PT, Bian JS (2009) Hydrogen sulfide inhibits rotenone-induced apoptosis via preservation of mitochondrial function. Mol Pharmacol 75:27–34
Kamoun P (2004) Endogenous production of hydrogen sulfide in mammals. Amino Acids 26:243–254
Kamoun P, Belardinelli MC, Chabli A, Lallouchi K, Chadefaux-Vekemans B (2003) Endogenous hydrogen sulfide overproduction in Down syndrome. Am J Med Genet A 116A:310–311
Kimura H (2000) Hydrogen sulfide induces cyclic AMP and modulates the NMDA receptor. Biochem Biophys Res Commun 267:129–133
Kimura H (2002) Hydrogen sulfide as a neuromodulator. Mol Neurobiol 26:13–19
Kimura Y, Kimura H (2004) Hydrogen sulfide protects neurons from oxidative stress. FASEB J 18:1165–1167
Kimura Y, Goto Y, Kimura H (2010) Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid Redox Signal 12:1–13
Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Bjorklund A (2003) Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci USA 100:2884–2889
Lowicka E, Beltowski J (2007) Hydrogen sulfide (H2S)—the third gas of interest for pharmacologists. Pharmacol Rep 59:4–24
Mitsuhashi H, Yamashita S, Ikeuchi H, Kuroiwa T, Kaneko Y, Hiromura K, Ueki K, Nojima Y (2005) Oxidative stress-dependent conversion of hydrogen sulfide to sulfite by activated neutrophils. Shock 24:529–534
Morrison LD, Smith DD, Kish SJ (1996) Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease. J Neurochem 67:1328–1331
Nakao A, Sugimoto R, Billiar TR, McCurry KR (2009) Therapeutic antioxidant medical gas. J Clin Biochem Nutr 44:1–13
Przedborski S, Vila M (2003) The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson’s disease. Ann N Y Acad Sci 991:189–198
Przedborski S, Tieu K, Perier C, Vila M (2004) MPTP as a mitochondrial neurotoxic model of Parkinson’s disease. J Bioenerg Biomembr 36:375–379
Qian JJ, Cheng YB, Yang YP, Mao CJ, Qin ZH, Li K, Liu CF (2008) Differential effects of overexpression of wild-type and mutant human alpha-synuclein on MPP+-induced neurotoxicity in PC12 cells. Neurosci Lett 435:142–146
Qu K, Chen CP, Halliwell B, Moore PK, Wong PT (2006) Hydrogen sulfide is a mediator of cerebral ischemic damage. Stroke 37:889–893
Rebois RV, Reynolds EE, Toll L, Howard BD (1980) Storage of dopamine and acetylcholine in granules of PC12, a clonal pheochromocytoma cell line. Biochemistry 19:1240–1248
Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346:476–483
Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, Kimura H (2009) 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 11:703–714
Szabo C (2007) Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 6:917–935
Tang XQ, Yang CT, Chen J, Yin WL, Tian SW, Hu B, Feng JQ, Li YJ (2008) Effect of hydrogen sulphide on beta-amyloid-induced damage in PC12 cells. Clin Exp Pharmacol Physiol 35:180–186
Walrand S, Valeix S, Rodriguez C, Ligot P, Chassagne J, Vasson MP (2003) Flow cytometry study of polymorphonuclear neutrophil oxidative burst: a comparison of three fluorescent probes. Clin Chim Acta 331:103–110
Wang R (2002) Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 16:1792–1798
Whiteman M, Armstrong JS, Chu SH, Jia-Ling S, Wong BS, Cheung NS, Halliwell B, Moore PK (2004) The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite ‘scavenger’? J Neurochem 90:765–768
Whiteman M, Cheung NS, Zhu YZ, Chu SH, Siau JL, Wong BS, Armstrong JS, Moore PK (2005) Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain? Biochem Biophys Res Commun 326:794–798
Whiteman M, Li L, Kostetski I, Chu SH, Siau JL, Bhatia M, Moore PK (2006) Evidence for the formation of a novel nitrosothiol from the gaseous mediators nitric oxide and hydrogen sulphide. Biochem Biophys Res Commun 343:303–310
Wu Y, Shang Y, Sun S, Liang H, Liu R (2007) Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/GSK-3beta/caspase-3 mediated signaling pathway. Apoptosis 12:1365–1375
Yamamoto N, Sawada H, Izumi Y, Kume T, Katsuki H, Shimohama S, Akaike A (2007) Proteasome inhibition induces glutathione synthesis and protects cells from oxidative stress: relevance to Parkinson disease. J Biol Chem 282:4364–4372
Yin WL, He JQ, Hu B, Jiang ZS, Tang XQ (2009) Hydrogen sulfide inhibits MPP(+)-induced apoptosis in PC12 cells. Life Sci 85:269–275
Acknowledgments
We thank Y. Wang for excellent revising. This study was supported by Natural Science Foundation of China (30770740), Natural Science Foundation of Hunan Province, China (06JJ2074), China Postdoctoral Science Foundation (2005038233), Plan Project for Scientific Research, Department of Science and Technology, Hunan Province (05FJ3039), and the Research Foundation of Education Bureau of Hunan Province (06C700).
Author information
Authors and Affiliations
Corresponding authors
Additional information
Xiao-Qing Tang and Li-Li Fan contributed equally to this work.
Rights and permissions
About this article
Cite this article
Tang, XQ., Fan, LL., Li, YJ. et al. Inhibition of Hydrogen Sulfide Generation Contributes to 1-Methy-4-Phenylpyridinium Ion-Induced Neurotoxicity. Neurotox Res 19, 403–411 (2011). https://doi.org/10.1007/s12640-010-9180-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-010-9180-4