Abstract
The present study was aimed at determining the role of paraquat (PQ) in the activation of the NF-E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway and the possible neuroprotective effects of tert-butylhydroquinone (tBHQ) pretreatment on PQ-induced neurodegeneration in vivo and in vitro. 7 mg/kg PQ treatment of male C57BL/6 mice caused decreased spontaneous locomotor activity, decreased tyrosine hydroxylase (TH)-positive neurons, increased terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end-labeling (TUNEL)-positive cells in the substantia nigra, as well as increased protein levels of both nuclear Nrf2 and HO-1. In PQ-treated mice, pretreatment with 1 % tBHQ (w/w) significantly attenuated impairments in behavioral performance, decreased TH-positive neurons, and increased TUNEL-positive cells in the substantia nigra, as well as increased protein expression of both nuclear Nrf2 and HO-1. Pretreatment with 40 μM tBHQ protected PC12 cells against 100 and 300 μM PQ-mediated cytotoxicity. The dual-luciferase reporter gene also revealed that the transcriptional activation of HO-1 gene expression of the antioxidant responsive element via Nrf2 occurred as a consequence of 100 and 300 μM PQ exposure. Collectively, these results clearly indicated for the first time that the Nrf2/HO-1 pathway in the substantia nigra was activated by PQ, and pretreatment with tBHQ conferred neuroprotection against PQ-induced Parkinsonism presumably by increasing Nrf2 and HO-1 expression.
Similar content being viewed by others
References
Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL (1999) Nrf2, a Cap‘n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 274:26071–26078
Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85:241–272
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306
Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee JM, Li J, Johnson JA (2009) The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal 11:497–508
Cao TT, Ma L, Kandpal G, Warren L, Hess JF, Seabrook GR (2005) Increased nuclear factor-erythroid 2 p45-related factor 2 activity protects SH-SY5Y cells against oxidative damage. J Neurochem 95:406–417
Cheung KL, Yu S, Pan Z, Ma J, Wu TY, Kong AN (2011) tBHQ-induced HO-1 expression is mediated by calcium through regulation of Nrf2 binding to enhancer and polymerase II to promoter region of HO-1. Chem Res Toxicol 24:670–676
Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909
Drechsel DA, Patel M (2008) Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radic Biol Med 44:1873–1886
Franklin KB, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San Diego
Hansen JM, Go YM, Jones DP (2006) Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling. Annu Rev Pharmacol Toxicol 46:215–234
Imhoff BR, Hansen JM (2010) Tert-butylhydroquinone induces mitochondrial oxidative stress causing Nrf2 activation. Cell Biol Toxicol 26:541–551
Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M (2000) Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275:16023–16029
Jin W, Kong J, Wang H, Wu J, Lu T, Jiang J, Ni H, Liang W (2011) Protective effect of tert-butylhydroquinone on cerebral inflammatory response following traumatic brain injury in mice. Injury 42:714–718
Kang MJ, Gil SJ, Koh HC (2009) Paraquat induces alternation of the dopamine catabolic pathways and glutathione levels in the substantia nigra of mice. Toxicol Lett 188:148–152
Kang MJ, Gil SJ, Lee JE, Koh HC (2010) Selective vulnerability of the striatal subregions of C57BL/6 mice to paraquat. Toxicol Lett 19:127–134
Kraft AD, Johnson DA, Johnson JA (2004) Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J Neurosci 24:1101–1112
Lee JM, Calkins MJ, Chan K, Kan YW, Johnson JA (2003a) Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem 278:12029–12038
Lee JM, Shih AY, Murphy TH, Johnson JA (2003b) NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J Biol Chem 278:37948–37956
Li J, Johnson D, Calkins M, Wright L, Svendsen C, Johnson J (2005a) Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci 83:313–328
Li X, Yin J, Cheng CM, Sun JL, Li Z, Wu YL (2005b) Paraquat induces selective dopaminergic nigrostriatal degeneration in aging C57BL/6 mice. Chin Med J 118:1357–1361
Li HY, Zhong YF, Wu SY, Shi N (2007a) NF-E2 related factor 2 activation and Heme oxygenase-1 induction by tert-butylhydroquinone protect against deltamethrin mediated oxidative stress in PC12 cells. Chem Res in Toxicol 20:1242–1251
Li HY, Wu SY, Shi N (2007b) Transcription factor Nrf2 activation by deltamethrin in PC12 cells: involvement of ROS. Toxico Lett 171:87–98
Li HY, Wu SY, Ma Q, Shi N (2011a) The pesticide deltamethrin increases free radical production and promotes nuclear translocation of the stress response transcription factor Nrf2 in rat brain. Toxicol Ind Health 27:579–590
Li H, Wu SY, Shi N, Lin W, You J, Zhou W (2011b) NF-E2-related factor 2 activation in PC12 cells: its protective role in manganese-induced damage. Arch Toxicol 85:901–910
Li HY, Wu SY, Lin W, Wang ZJ, Ye PL, Han QF (2011c) Antagonism of tert-butylhydroquinone on neurotoxicity and oxidative stress induced by paraquat in PC12. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 29:270–274
Liou HH, Chen RC, Tsai YF, Chen WP, Chang YC, Tsai MC (1996) Effects of paraquat on the substantia nigra of the Wistar rats: neurochemical, histological, and behavioral studies. Toxicol Appl Pharmacol 137:34–41
Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, Chen RC (1997) Environmental risk factors and Parkinson‘s disease: a case-control study in Taiwan. Neurology 48:1583–1588
Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of a-synuclein in mice. J Biol Chem 277:1641–1644
McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta D, Di Monte DA (2002) Environmental risk factors and Parkinson‘s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 19:119–127
McCormack AL, Atienza JG, Johnston LC, Andersen JK, Vu S, Di Monte DA (2005) Role of oxidative stress in paraquat-induced dopaminergic cell degeneration. J Neurochem 93:1030–1037
Miller RL, James-Kracke M, Sun GY, Sun AY (2009) Oxidative and inflammatory pathways in Parkinson’s disease. Neurochem Res 34:55–65
Minelli A, Conte C, Grottelli S, Bellezza I, Emiliani C, Bolaños JP (2009) Cyclo(His-Pro) up-regulates heme oxygenase 1 via activation of Nrf2-ARE signalling. J Neurochem 111:956–966
Nouhi F, Tusi SK, Abdi A, Khodagholi F (2011) Dietary supplementation with tBHQ, an Nrf2 stabilizer molecule, confers neuroprotection against apoptosis in amyloid β-injected rat. Neurochem Res 36:870–878
Peng J, Mao XO, Stevenson FF, Hsu M, Andersen JK (2004) The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway. J Biol Chem 279:32626–32632
Shafer TJ, Atchison WD (1991) Transmitter, ion channel and receptor properties of pheochromocytoma (PC12) cells: a model for neurotoxicological studies. NeuroToxicology 12:473–492
Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23:3394–3406
Shih AY, Li P, Murphy TH (2005a) A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J Neurosci 25:10321–10335
Shih AY, Imbeault S, Barakauskas V, Erb H, Jiang L, Li P, Murphy TH (2005b) Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J Biol Chem 280:22925–22936
Toulouse A, Sullivan AM (2008) Progress in Parkinson’s disease-where do we stand? Prog Neurobiol 85:376–392
Yang WL, Sun AY (1998) Paraquat-induced cell death in PC12 cells. Neurochem Res 23:1387–1394
Yang W, Tiffany-Castiglioni E, Lee MY, Son IH (2010) Paraquat induces cyclooxygenase-2 (COX-2) implicated toxicity in human neuroblastoma SH-SY5Y cells. Toxicol Lett 199:239–246
Zhao J, Kobori N, Aronowski J, Dash PK (2006) Sulforaphane reduces infarct volume following focal cerebral ischemia in rodents. Neurosci Lett 393:108–112
Acknowledgments
This work was supported by the National Natural Science Foundation in China (Grant 30800936, 81172715), Fujian Province Funds for Distinguished Young Scientists (2012J06018) and by Program for New Century Excellent Talents in Fujian Province University (NCETFJ, JA11103).
Conflict of interest
All authors declare that there are no conflicts of interest in this study.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Li, H., Wu, S., Wang, Z. et al. Neuroprotective effects of tert-butylhydroquinone on paraquat-induced dopaminergic cell degeneration in C57BL/6 mice and in PC12 cells. Arch Toxicol 86, 1729–1740 (2012). https://doi.org/10.1007/s00204-012-0935-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-012-0935-y