Abstract
ACS6, a novel hydrogen sulfide (H2S)-releasing sildenafil, has been demonstrated to inhibit superoxide formation through donating H2S. We have previously found that ACS6 antagonizes homocysteine-induced apoptosis and cytotoxicity. The aim of the present study is to explore the molecular mechanisms underlying ACS6-exerted protective action against the neurotoxicity of homocysteine. In the present work, we used PC12 cells to explore whether paraoxonase-1 (PON-1) is implicated in ACS6-induced neuroprotection against homocysteine neurotoxicity. We show that ACS6 treatment results in prevention of homocysteine-caused neurotoxicity and overproduction of reactive oxygen species (ROS). Homocysteine downregulates the expression and activity of PON-1; however, this effect is significantly blocked by co-treatment with ACS6. The specific inhibitor of PON-1 2-hydroxyquinoline reverses the inhibitory effect of ACS6 on homocysteine-induced neurotoxicity and intracellular ROS accumulation. These results indicate that ACS6 protects PC12 cells against homocysteine-induced neurotoxicity by upregulating PON-1 and suggest a promising role of PON-1 as a novel therapeutic strategy for homocysteine-induced toxicity.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ataie A, Sabetkasaei M, Haghparast A, Moghaddam AH, Ataee R, Moghaddam SN (2010) Curcumin exerts neuroprotective effects against homocysteine intracerebroventricular injection-induced cognitive impairment and oxidative stress in rat brain. J Med Food 13:821–826
Aviram M, Rosenblat M (2005) Paraoxonases and cardiovascular diseases: pharmacological and nutritional influences. Curr Opin Lipidol 16:393–399
Aviram M, Rosenblat M, Billecke S, Erogul J, Sorenson R, Bisgaier CL, Newton RS, La Du B (1999) Human serum paraoxonase (PON 1) is inactivated by oxidized low density lipoprotein and preserved by antioxidants. Free Radic Biol Med 26:892–904
Borowczyk K, Shih DM, Jakubowski H (2012) Metabolism and neurotoxicity of homocysteine thiolactone in mice: evidence for a protective role of paraoxonase 1. J Alzheimers Dis. doi:10.3233/JAD-2012-111940
Cathcart R, Schwiers E, Ames BN (1983) Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay. Anal Biochem 134:111–116
Chasse JF (2005) Inverse correlation between phenylacetate hydrolase activity of the serum PON1 protein and homocysteinemia in humans. Thromb Haemost 93:182–183
Christie LA, Riedel G, Algaidi SA, Whalley LJ, Platt B (2005) Enhanced hippocampal long-term potentiation in rats after chronic exposure to homocysteine. Neurosci Lett 373:119–124
Grieve A, Butcher SP, Griffiths R (1992) Synaptosomal plasma membrane transport of excitatory sulphur amino acid transmitter candidates: kinetic characterisation and analysis of carrier specificity. J Neurosci Res 32:60–68
Hamelet J, Ait-Yahya-Graison E, Matulewicz E, Noll C, Badel-Chagnon A, Camproux AC, Demuth K, Paul JL, Delabar JM, Janel N (2007) Homocysteine threshold value based on cystathionine beta synthase and paraoxonase 1 activities in mice. Eur J Clin Invest 37:933–938
Heinecke JW, Rosen H, Suzuki LA, Chait A (1987) The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem 262:10098–10103
Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers E, Shea TB (2001) Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem 78:249–253
Ho YS, Yu MS, Yang XF, So KF, Yuen WH, Chang RC (2010) Neuroprotective effects of polysaccharides from wolfberry, the fruits of Lycium barbarum, against homocysteine-induced toxicity in rat cortical neurons. J Alzheimers Dis 19:813–827
Hooshmand B, Solomon A, Kareholt I, Leiviska J, Rusanen M, Ahtiluoto S, Winblad B, Laatikainen T, Soininen H, Kivipelto M (2010) Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology 75:1408–1414
Isobe C, Abe T, Terayama Y (2009) Homocysteine may contribute to pathogenesis of RNA damage in brains with Alzheimer’s disease. Neurodegener Dis 6:252–257
Jakubowski H (2010) The role of paraoxonase 1 in the detoxification of homocysteine thiolactone. Adv Exp Med Biol 660:113–127
Karikas GA, Kriebardis A, Samara I, Schulpis K, Papachristodoulou M, Fytou-Pallikari A (2006) Serum homocysteine levels and paraoxonase 1 activity in preschool aged children in Greece. Clin Chem Lab Med 44:623–627
Kim JH, Cho SY, Lee JH, Jeong SM, Yoon IS, Lee BH, Pyo MK, Lee SM, Chung JM, Kim S, Rhim H, Oh JW, Nah SY (2007) Neuroprotective effects of ginsenoside Rg3 against homocysteine-induced excitotoxicity in rat hippocampus. Brain Res 1136:190–199
Kim HJ, Cho HK, Kwon YH (2008) Synergistic induction of ER stress by homocysteine and beta-amyloid in SH-SY5Y cells. J Nutr Biochem 19:754–761
Kuszczyk M, Gordon-Krajcer W, Lazarewicz JW (2009) Homocysteine-induced acute excitotoxicity in cerebellar granule cells in vitro is accompanied by PP2A-mediated dephosphorylation of tau. Neurochem Int 55:174–180
Leduc V, Theroux L, Dea D, Robitaille Y, Poirier J (2009) Involvement of paraoxonase 1 genetic variants in Alzheimer’s disease neuropathology. Eur J Neurosci 30:1823–1830
Li L, Whiteman M, Guan YY, Neo KL, Cheng Y, Lee SW, Zhao Y, Baskar R, Tan CH, Moore PK (2008) Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation 117:2351–2360
Loureiro SO, Heimfarth L, Pelaez Pde L, Vanzin CS, Viana L, Wyse AT, Pessoa-Pureur R (2008) Homocysteine activates calcium-mediated cell signaling mechanisms targeting the cytoskeleton in rat hippocampus. Int J Dev Neurosci 26:447–455
Marsillach J, Mackness B, Mackness M, Riu F, Beltran R, Joven J, Camps J (2008) Immunohistochemical analysis of paraoxonases-1, 2, and 3 expression in normal mouse tissues. Free Radic Biol Med 45:146–157
Muzaffar S, Jeremy JY, Sparatore A, Del Soldato P, Angelini GD, Shukla N (2008) H2S-donating sildenafil (ACS6) inhibits superoxide formation and gp91phox expression in arterial endothelial cells: role of protein kinases A and G. Br J Pharmacol 155:984–994
Ng CJ, Shih DM, Hama SY, Villa N, Navab M, Reddy ST (2005) The paraoxonase gene family and atherosclerosis. Free Radic Biol Med 38:153–163
Oldreive CE, Doherty GH (2007) Neurotoxic effects of homocysteine on cerebellar Purkinje neurons in vitro. Neurosci Lett 413:52–57
Park YJ, Jang Y, Kwon YH (2010) Protective effect of isoflavones against homocysteine-mediated neuronal degeneration in SH-SY5Y cells. Amino Acids 39:785–794
Perna AF, Ingrosso D, De Santo NG (2003) Homocysteine and oxidative stress. Amino Acids 25:409–417
Prudova A, Bauman Z, Braun A, Vitvitsky V, Lu SC, Banerjee R (2006) S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity. Proc Natl Acad Sci USA 103:6489–6494
Qu K, Lee SW, Bian JS, Low CM, Wong PT (2008) Hydrogen sulfide: neurochemistry and neurobiology. Neurochem Int 52:155–165
Rajagopalan P, Hua X, Toga AW, Jack CR Jr, Weiner MW, Thompson PM (2011) Homocysteine effects on brain volumes mapped in 732 elderly individuals. Neuroreport 22:391–395
Rozenberg O, Shiner M, Aviram M, Hayek T (2008) Paraoxonase 1 (PON1) attenuates diabetes development in mice through its antioxidative properties. Free Radic Biol Med 44:1951–1959
Selhub J (1999) Homocysteine metabolism. Annu Rev Nutr 19:217–246
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
Smach MA, Jacob N, Golmard JL, Charfeddine B, Lammouchi T, Ben Othman L, Dridi H, Bennamou S, Limem K (2011) Folate and homocysteine in the cerebrospinal fluid of patients with Alzheimer’s disease or dementia: a case control study. Eur Neurol 65:270–278
Szabo C (2007) Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 6:917–935
Tan BH, Wong PT, Bian JS (2010) Hydrogen sulfide: a novel signaling molecule in the central nervous system. Neurochem Int 56:3–10
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
Tang XQ, Shen XT, Huang YE, Ren YK, Chen RQ, Hu B, He JQ, Yin WL, Xu JH, Jiang ZS (2010) Hydrogen sulfide antagonizes homocysteine-induced neurotoxicity in PC12 cells. Neurosci Res 68:241–249
Tang XQ, Chen RQ, Ren YK, Soldato PD, Sparatore A, Zhuang YY, Fang HR, Wang CY (2011a) ACS6, a hydrogen sulfide-donating derivative of sildenafil, inhibits homocysteine-induced apoptosis by preservation of mitochondrial function. Med Gas Res 1:20
Tang XQ, Fan LL, Li YJ, Shen XT, Zhuan YY, He JQ, Xu JH, Hu B (2011b) Inhibition of hydrogen sulfide generation contributes to 1-methy-4-phenylpyridinium ion-induced neurotoxicity. Neurotox Res 19:403–411
Thiersch M, Raffelsberger W, Frigg R, Samardzija M, Wenzel A, Poch O, Grimm C (2008) Analysis of the retinal gene expression profile after hypoxic preconditioning identifies candidate genes for neuroprotection. BMC Genomics 9:73
Uzun H, Yanardag H, Gelisgen R, Genc H, Uygun S, Vehid S, Karter Y, Demirci S (2008) Levels of paraoxonase, an index of antioxidant defense, in patients with active sarcoidosis. Curr Med Res Opin 24:1651–1657
Van Dam F, Van Gool WA (2009) Hyperhomocysteinemia and Alzheimer’s disease: a systematic review. Arch Gerontol Geriatr 48:425–430
Wehr H, Bednarska-Makaruk M, Graban A, Lipczynska-Lojkowska W, Rodo M, Bochynska A, Ryglewicz D (2009) Paraoxonase activity and dementia. J Neurol Sci 283:107–108
White AR, Huang X, Jobling MF, Barrow CJ, Beyreuther K, Masters CL, Bush AI, Cappai R (2001) Homocysteine potentiates copper- and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer’s-type neurodegenerative pathways. J Neurochem 76:1509–1520
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
Yan SK, Chang T, Wang H, Wu L, Wang R, Meng QH (2006) Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells. Biochem Biophys Res Commun 351:485–491
Yildiz H, Durmus AS, Simsek H, Yaman I (2011) Effects of sildenafil citrate on torsion/detorsion-induced changes in red blood cell and plasma lipid peroxidation, antioxidants, and blood hematology of male rats. Eur J Obstet Gynecol Reprod Biol 159:359–363
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
Zhuo JM, Wang H, Pratico D (2011) Is hyperhomocysteinemia an Alzheimer’s disease (AD) risk factor, an AD marker, or neither? Trends Pharmacol Sci 32:562–571
Acknowledgments
This study was supported by the Natural Science Foundation of China (81071005, 30770740) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry ([2010]508).
Author information
Authors and Affiliations
Corresponding authors
Additional information
Xiao-Qing Tang and Rong-Qian Chen have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Tang, XQ., Chen, RQ., Dong, L. et al. Role of Paraoxonase-1 in the Protection of Hydrogen Sulfide-Donating Sildenafil (ACS6) Against Homocysteine-Induced Neurotoxicity. J Mol Neurosci 50, 70–77 (2013). https://doi.org/10.1007/s12031-012-9862-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-012-9862-x