Abstract
Pramipexole, a novel non-ergot dopamine (DA) agonist, has been successfully applied to the treatment of Parkinson’s disease (PD). Although the specific cause of PD remains unknown, recent studies have provided evidence that oxidative stress plays a role in the parthenogenesis of the disease. In the present study, we examined the effect of pramipexole on hydrogen peroxide (H2O2, 100 μM)-induced PC12 cell death, and the intracellular mechanism of this effect. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay revealed that pretreatment of PC12 cells with pramipexole (1–100 μM) resulted in significant protection against H2O2-induced cell death in a concentration-dependent manner. The protective effect of pramipexole was not affected by pretreatment with the DA receptor antagonists sulpiride, spiperone or domperidone, suggesting that the effect of pramipexole is not mediated by DA receptors. In PC12 cells, pramipexole inhibited H2O2-induced lactate dehydrogenase (LDH) leakage, as well as H2O2-induced cytochrome c release and caspase-3 activation with the resultant apoptosis. It was also observed in PC12 cells that H2O2 stimulated phosphorylation of mitogen-activated protein (MAP) kinases, i.e., extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase. Pramipexole inhibited H2O2-induced JNK and p38 MAP kinase, but not ERK1/2 phosphorylation. Furthermore, in these cells experiments with a fluorescent probe, 2-[6-(4'-amino)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid, revealed that pramipexole, the JNK inhibitor SP600125 and the p38 MAP kinase inhibitor SB203580 inhibited the generation of H2O2-induced reactive oxygen species. Caspase inhibitors Z-DEVD-FMK and Z-IETD-FMK, as well as SP600125 and SB203580, inhibited H2O2-induced PC12 cell death to a similar extent as pramipexole. These results suggest that pramipexole exerts a protective effect against oxidative stress-induced PC12 cell death in part through an inhibition of JNK and p38 MAP kinase.
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References
Abramova NA, Cassarino DS, Khan SM, Painter TW and Bennett JP, Jr. (2002) Inhibition by R(+) or S(-) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma. J Neurosci Res 67:494–500
Ali N, Yoshizumi M, Tsuchiya K, Kyaw M, Fujita Y, Izawa Y, Abe S, Kanematsu Y, Kagami S and Tamaki T (2004) Ebselen inhibits p38 mitogen-activated protein kinasemediated endothelial cell death by hydrogen peroxide. Eur J Pharmacol 485:127–135
Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10 Suppl:S18–S25
Bennett JP, Jr. and Piercey MF (1999) Pramipexole–a new dopamine agonist for the treatment of Parkinson’s disease. J Neurol Sci 163:25–31
Callsen D and Brune B (1999) Role of mitogen-activated protein kinases in S-nitrosoglutathione-induced macrophage apoptosis. Biochemistry 38:2279–2286
Cassarino DS, Fall CP, Smith TS and Bennett JP, Jr. (1998) Pramipexole reduces reactive oxygen species production in vivo and in vitro and inhibits the mitochondrial permeability transition produced by the parkinsonian neurotoxin methylpyridinium ion. J Neurochem 71:295–301
Chan PH (1996) Role of oxidants in ischemic brain damage. Stroke 27:1124–1129
Choi HJ, Lee SY, Cho Y and Hwang O (2004) JNK activation by tetrahydrobiopterin: implication for Parkinson’s disease. J Neurosci Res 75:715–721
Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326 (Pt 1):1–16
Earnshaw WC, Martins LM and Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 68:383–424
Fahn S and Cohen G (1992) The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 32:804–812
Ferger B, Teismann P and Mierau J (2000) The dopamine agonist pramipexole scavenges hydroxyl free radicals induced by striatal application of 6-hydroxydopamine in rats: an in vivo microdialysis study. Brain Res 883:216–223
Ferrer I, Blanco R, Carmona M, Puig B, Barrachina M, Gomez C and Ambrosio S (2001) Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson’s disease and Dementia with Lewy bodies. J Neural Transm 108:1383–1396
Green DR and Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312
Gu M, Iravani MM, Cooper JM, King D, Jenner P and Schapira AH (2004) Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms. J Neurochem 91:1075–1081
Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59:1609–1623
Halliwell B and Aruoma OI (1991) DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS Lett 281:9–19
Ham J, Eilers A, Whitfield J, Neame SJ and Shah B (2000) c-Jun and the transcriptional control of neuronal apoptosis. Biochem Pharmacol 60:1015–1021
Harada J and Sugimoto M (1999) An inhibitor of p38 and JNK MAP kinases prevents activation of caspase and apoptosis of cultured cerebellar granule neurons. Jpn J Pharmacol 79:369–378
Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BA, Mouatt-Prigent A, Turmel H, Srinivasan A, Ruberg M, Evan GI, Agid Y and Hirsch EC (2000) Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci U S A 97:2875–2880
Hou RC, Huang HM, Tzen JT and Jeng KC (2003) Protective effects of sesamin and sesamolin on hypoxic neuronal and PC12 cells. J Neurosci Res 74:123–133
Jacobson MD (1996) Reactive oxygen species and programmed cell death. Trends Biochem Sci 21:83–86
Jenner P and Olanow CW (1998) Understanding cell death in Parkinson’s disease. Ann Neurol 44:S72–S84
Jeon BS, Kholodilov NG, Oo TF, Kim SY, Tomaselli KJ, Srinivasan A, Stefanis L and Burke RE (1999) Activation of caspase-3 in developmental models of programmed cell death in neurons of the substantia nigra. J Neurochem 73:322–333
Kakimura J, Kitamura Y, Takata K, Kohno Y, Nomura Y and Taniguchi T (2001) Release and aggregation of cytochrome c and alpha-synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole. Eur J Pharmacol 417:59–67
Kitamura Y, Kosaka T, Kakimura JI, Matsuoka Y, Kohno Y, Nomura Y and Taniguchi T (1998) Protective effects of the antiparkinsonian drugs talipexole and pramipexole against 1-methyl-4-phenylpyridinium-induced apoptotic death in human neuroblastoma SH-SY5Y cells. Mol Pharmacol 54:1046–1054
Koyama AH, Akari H, Adachi A, Goshima F and Nishiyama Y (1998) Induction of apoptosis in HEp-2 cells by infection with herpes simplex virus type 2. Arch Virol 143:2435–2441
Kulich SM and Chu CT (2001) Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: implications for Parkinson’s disease. J Neurochem 77:1058–1066
Kyriakis JM and Avruch J (1996) Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem 271:24313–24316
Lange KW (1998) Clinical pharmacology of dopamine agonists in Parkinson’s disease. Drugs Aging 13:381–389
Le WD, Jankovic J, Xie W and Appel SH (2000) Antioxidant property of pramipexole independent of dopamine receptor activation in neuroprotection. J Neural Transm 107:1165–1173
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES and Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489
Matsura T, Kai M, Fujii Y, Ito H and Yamada K (1999) Hydrogen peroxide-induced apoptosis in HL-60 cells requires caspase-3 activation. Free Radic Res 30:73–83
Nair VD, Olanow CW and Sealfon SC (2003) Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in dopaminergic cell lines. Biochem J 373:25–32
Olanow CW, Jenner P and Brooks D (1998) Dopamine agonists and neuroprotection in Parkinson’s disease. Ann Neurol 44:S167–S174
Ramirez AD, Wong SK and Menniti FS (2003) Pramipexole inhibits MPTP toxicity in mice by dopamine D3 receptor dependent and independent mechanisms. Eur J Pharmacol 475:29–35
Rascol O (2000) The pharmacological therapeutic management of levodopa-induced dyskinesias in patients with Parkinson’s disease. J Neurol 247 Suppl 2:II51–57
Sawada H, Ibi M, Kihara T, Urushitani M, Akaike A, Kimura J and Shimohama S (1998) Dopamine D2-type agonists protect mesencephalic neurons from glutamate neurotoxicity: mechanisms of neuroprotective treatment against oxidative stress. Ann Neurol 44:110–119
Schapira AH (2002) Neuroprotection and dopamine agonists. Neurology 58:S9–S18
Setsukinai K, Urano Y, Kakinuma K, Majima HJ and Nagano T (2003) Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species. J Biol Chem 278:3170–3175
Song BJ, Soh Y, Bae M, Pie J, Wan J and Jeong K (2001) Apoptosis of PC12 cells by 4-hydroxy-2-nonenal is mediated through selective activation of the c-Jun N-terminal protein kinase pathway. Chem Biol Interact 130–132:943–954
Tabner BJ, Turnbull S, El-Agnaf OM and Allsop D (2002) Formation of hydrogen peroxide and hydroxyl radicals from A(beta) and alpha-synuclein as a possible mechanism of cell death in Alzheimer’s disease and Parkinson’s disease. Free Radic Biol Med 32:1076–1083
Tibbles LA and Woodgett JR (1999) The stress-activated protein kinase pathways. Cell Mol Life Sci 55:1230–1254
Traver S, Salthun-Lassalle B, Marien M, Hirsch EC, Colpaert F and Michel PP (2005) The neurotransmitter noradrenaline rescues septal cholinergic neurons in culture from degeneration caused by low-level oxidative stress. Mol Pharmacol 67:1882–1891
Troadec JD, Marien M, Darios F, Hartmann A, Ruberg M, Colpaert F and Michel PP (2001) Noradrenaline provides long-term protection to dopaminergic neurons by reducing oxidative stress. J Neurochem 79:200–210
Tschopp J, Thome M, Hofmann K and Meinl E (1998) The fight of viruses against apoptosis. Curr Opin Genet Dev 8:82–87
Widmann C, Gibson S, Jarpe MB and Johnson GL (1999) Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 79:143–180
Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331
Yoshizumi M, Kogame T, Suzaki Y, Fujita Y, Kyaw M, Kirima K, Ishizawa K, Tsuchiya K, Kagami S and Tamaki T (2002a) Ebselen attenuates oxidative stress-induced apoptosis via the inhibition of the c-Jun N-terminal kinase and activator protein-1 signalling pathway in PC12 cells. Br J Pharmacol 136:1023–1032
Yoshizumi M, Tsuchiya K, Suzaki Y, Kirima K, Kyaw M, Moon JH, Terao J and Tamaki T (2002b) Quercetin glucuronide prevents VSMC hypertrophy by angiotensin II via the inhibition of JNK and AP-1 signaling pathway. Biochem Biophys Res Commun 293:1458–1465
Zou L, Jankovic J, Rowe DB, Xie W, Appel SH and Le W (1999) Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity. Life Sci 64:1275–1285
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Fujita, Y., Izawa, Y., Ali, N. et al. Pramipexole protects against H2O2-induced PC12 cell death. Naunyn Schmied Arch Pharmacol 372, 257–266 (2006). https://doi.org/10.1007/s00210-005-0025-2
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DOI: https://doi.org/10.1007/s00210-005-0025-2