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Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

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Abstract

Valproic acid (VPA), an established antiepileptic and antimanic drug, has recently emerged as a promising neuroprotective agent. Among its many cellular targets, VPA has been recently demonstrated to be an effective inhibitor of histone deacetylases. Accordingly, we have adopted a schedule of dietary administration (2% VPA added to the chow) that results in a significant inhibition of histone deacetylase activity and in an increase of histone H3 acetylation in brain tissues of 4 weeks-treated rats. We have tested this schedule of VPA treatment in an animal model of Parkinson’s disease (PD), in which degeneration of nigro-striatal dopaminergic neurons is obtained through sub-chronic administration of the mitochondrial toxin, rotenone, via osmotic mini pumps implanted to rats. The decrease of the dopaminergic marker tyrosine hydroxylase in substantia nigra and striatum caused by 7 days toxin administration was prevented in VPA-fed rats. VPA treatment also significantly counteracted the death of nigral neurons and the 50% drop of striatal dopamine levels caused by rotenone administration. The PD-marker protein α-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated α-synuclein increased in the same regions. VPA treatment counteracted both these α-synuclein alterations. Furthermore, monoubiquitinated α-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of α-synuclein has been recently described in some models of PD and its neurodegenerative effect has been ascribed to histone acetylation inhibition. Thus, the ability of VPA to increase histone acetylation is a novel candidate mechanism for its neuroprotective action.

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Abbreviations

VPA:

Valproic acid

PD:

Parkinson’s disease

TH:

Tyrosine hydroxylase

HDAC:

Histone deacetylase

MPP+ :

1-Methyl-phenylpyridinium

6-OHDA:

6-Hydrohydopamine

DMSO:

Dimethylsulfoxide

PEG:

Polyethylene-glycol

DOPAC:

Dihydroxyphenyl acetic acid

HVA:

Homovanillic acid

References

  • Alves Da Costa C, Paitel E, Vincent B, Checler F (2002) Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. Abolishment by 6-hydroxydopamine and implication for Parkinson’s disease. J Biol Chem 277:50980–50984

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Bialer M, Yagen B (2007) Valproic acid: second generation. Neurotherapeutics 4:130–137

    Article  CAS  PubMed  Google Scholar 

  • Bowden CL (2003) Valproate. Bipol Disord. 5:189–202

    Article  CAS  Google Scholar 

  • Caruccio L, Banerjee R (1999) An efficient method for simultaneous isolation of biologically active transcription factors and DNA. J Immunol Methods 230:1–10

    Article  CAS  PubMed  Google Scholar 

  • Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC, Wilson B, Lu RB, Gean PW, Chuang DM, Hong JS (2006) Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry 11:1116–1125

    Article  CAS  PubMed  Google Scholar 

  • Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H, Lu RB, Gean PW, Chuang DM, Hong JS (2007) Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience 149:203–212

    Article  CAS  PubMed  Google Scholar 

  • Chuang DM (2005) The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann N Y Acad Sci 1053:195–204

    Article  CAS  PubMed  Google Scholar 

  • D’Souza A, Onem E, Patel P, La Gamma EF, Nankova BB (2009) Valproic acid regulates catecholaminergic pathways by concentration-dependent threshold effects on TH mRNA synthesis and degradation. Brain Res 1247:1–10

    Article  PubMed  CAS  Google Scholar 

  • DeCastro M, Nankova BB, Shah P, Patel P, Mally PV, Mishra R, La Gamma EF (2005) Short chain fatty acids regulate tyrosine hydroxylase gene expression through a cAMP-dependent signaling pathway. Mol Brain Res 142:28–38

    Article  CAS  PubMed  Google Scholar 

  • Eleuteri S, Monti B, Brignani S, Contestabile A (2009) Chronic dietary administration of valproic acid protects neurons of the rat nucleus basalis magnocellularis from ibotenic acid neurotoxicity. Neurotox Res 15:127–132

    Article  CAS  PubMed  Google Scholar 

  • Engelender S (2008) Ubiquitination of alpha-synuclein and autophagy in Parkinson’s disease. Autophagy 4:372–374

    CAS  PubMed  Google Scholar 

  • Feng Y, Liang ZH, Wang T, Qiao X, Liu HJ, Sun SG (2006) Alpha-synuclein redistributed and aggregated in rotenone-induced Parkinson’s disease rats. Neurosci Bull 22:288–293

    CAS  PubMed  Google Scholar 

  • Fountoulakis KN, Vieta E, Sanchez-Moreno J, Kaprinis SG, Goikolea JM, Kaprinis GS (2005) Treatment guidelines for bipolar disorder: a critical review. J Affect Disord 86:1–10

    Article  CAS  PubMed  Google Scholar 

  • Goers J, Manning-Bog AB, McCormack AL, Millett IS, Doniach S, Di Monte DA, Uversky VN, Fink AL (2003) Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry 42:8465–8671

    Article  CAS  PubMed  Google Scholar 

  • Göttlicher M (2004) Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. Ann Hematol 83:S91–S92

    PubMed  Google Scholar 

  • Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20:6969–6978

    Article  PubMed  Google Scholar 

  • Grossi G, Bargossi AM, Lucarelli C, Paradisi R, Sprovieri C, Sprovieri G (1991) Improvements in automated analysis of catecholamines and related metabolites in biological samples by column-switching high-performance liquid chromatography. J Chromatogr 541:273–284

    Article  CAS  PubMed  Google Scholar 

  • Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G (2004) Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci 24:6590–6599

    Article  CAS  PubMed  Google Scholar 

  • Hicke L (2001) Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2:195–201

    Article  CAS  PubMed  Google Scholar 

  • Jensen PJ, Alter BJ, O’Malley KL (2003) Alpha-synuclein protects naive but not dbcAMP-treated dopaminergic cell types from 1-methyl-4-phenylpyridinium toxicity. J Neurochem 86:196–209

    Article  CAS  PubMed  Google Scholar 

  • Jeong MR, Hashimoto R, Senatorov VV, Fujimaki K, Ren M, Lee MS, Chuang DM (2003) Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition. FEBS Lett 542:74–78

    Article  CAS  PubMed  Google Scholar 

  • Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther 321(3):892–901

    Article  CAS  PubMed  Google Scholar 

  • Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Björklund A (2002) Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22:2780–2791

    CAS  PubMed  Google Scholar 

  • Kontopoulos E, Parvin JD, Feany MB (2006) Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15:3012–3023

    Article  CAS  PubMed  Google Scholar 

  • Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108

    Article  PubMed  Google Scholar 

  • Leng Y, Chuang DM (2006) Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity. J Neurosci 26:7502–7512

    Article  CAS  PubMed  Google Scholar 

  • Lin WL, DeLucia MW, Dickson DW (2004) Alpha-synuclein immunoreactivity in neuronal nuclear inclusions and neurites in multiple system atrophy. Neurosci Lett 354:99–102

    Article  CAS  PubMed  Google Scholar 

  • Löscher W (2002) Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16:669–694

    Article  PubMed  Google Scholar 

  • Lowry OH, Rosenbrough RJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Manji HK, Bebchuk JM, Moore GJ, Glitz D, Hasanat KA, Chen G (1999) Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents: therapeutic implications. J Clin Psychiatry 60:27–39

    PubMed  Google Scholar 

  • Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA (2003) Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 23:3095–3099

    CAS  PubMed  Google Scholar 

  • Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815

    CAS  PubMed  Google Scholar 

  • Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269

    Article  CAS  PubMed  Google Scholar 

  • Matsuoka Y, Vila M, Lincoln S, McCormack A, Picciano M, LaFrancois J, Yu X, Dickson D, Langston WJ, McGowan E, Farrer M, Hardy J, Duff K, Przedborski S, Di Monte DA (2001) Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 8:535–539

    Article  CAS  PubMed  Google Scholar 

  • McElroy SL, Keck PE (1995) Misattribution of eating and obsessive-compulsive disorder symptoms to repressed memories of childhood sexual or physical abuse. Biol Psychiatry 37:48–51

    Article  CAS  PubMed  Google Scholar 

  • Meurers BH, Zhu C, Fernagut PO, Richter F, Hsia YC, Fleming SM, Oh M, Elashoff D, Dicarlo CD, Seaman RL, Chesselet MF (2008) Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo. Neurobiol Dis 33:182–192

    Article  PubMed  CAS  Google Scholar 

  • Monti B, Contestabile A (2003) Selective alteration of DNA fragmentation and caspase activity in the spinal cord of aged rats and effect of dietary restriction. Brain Res 992:137–141

    Article  CAS  PubMed  Google Scholar 

  • Monti B, Polazzi E, Batti L, Crochemore C, Virgili M, Contestabile A (2007) Alpha-synuclein protects cerebellar granule neurons against 6-hydroxydopamine-induced death. J Neurochem 103:518–530

    Article  CAS  PubMed  Google Scholar 

  • Monti B, Polazzi E, Contestabile A (2009) Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection. Curr Mol Pharmacol 2:95–109

    Article  CAS  PubMed  Google Scholar 

  • Morland C, Boldingh KA, Iversen EG, Hassel B (2004) Valproate is neuroprotective against malonate toxicity in rat striatum: an association with augmentation of high-affinity glutamate uptake. J Cereb Blood Flow Metab 24(11):1226–1234

    Article  CAS  PubMed  Google Scholar 

  • Norris EH, Giasson BI, Lee VM (2004) Alpha-synuclein: normal function and role in neurodegenerative diseases. Curr Top Dev Biol 60:17–54

    Article  CAS  PubMed  Google Scholar 

  • Nutt J, Williams A, Plotkin C, Eng N, Ziegler M, Calne DB (1979) Treatment of Parkinson’s disease with sodium valproate: clinical, pharmacological, and biochemical observations. Can J Neurol Sci 6:337–343

    CAS  PubMed  Google Scholar 

  • Pan T, Li X, Xie W, Jankovic J, Le W (2005) Valproic acid-mediated Hsp70 induction and anti-apoptotic neuroprotection in SH-SY5Y cells. FEBS Lett 579:6716–6720

    Article  CAS  PubMed  Google Scholar 

  • Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741

    Article  CAS  PubMed  Google Scholar 

  • Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    Article  CAS  PubMed  Google Scholar 

  • Price PA, Parkes JD, Marsden CD (1978) Sodium valproate in the treatment of levodopa-induced dyskinesia. J Neurol Neurosurg Psychiatr 41:702–706

    Article  CAS  PubMed  Google Scholar 

  • Rathke-Hartlieb S, Kahle PJ, Neumann M, Ozmen L, Haid S, Okochi M, Haass C, Schulz JB (2001) Sensitivity to MPTP is not increased in Parkinson’s disease-associated mutant alpha-synuclein transgenic mice. J Neurochem 77:1181–1184

    Article  CAS  PubMed  Google Scholar 

  • Rogawski MA, Löscher W (2004) The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5:553–564

    Article  CAS  PubMed  Google Scholar 

  • Rott R, Szargel R, Haskin J, Shani V, Shainskaya A, Manov I, Liani E, Avraham E, Engelender S (2008) Monoubiquitylation of alpha-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells. J Biol Chem 283:3316–3328

    Article  CAS  PubMed  Google Scholar 

  • Salmena L, Pandolfi PP (2007) Changing venues for tumour suppression: balancing destruction and localization by monoubiquitylation. Nat Rev Cancer 7:409–413

    Article  CAS  PubMed  Google Scholar 

  • Sands SA, Guerra V, Morilak DA (2000) Changes in tyrosine hydroxylase mRNA expression in the rat locus coeruleus following acute or chronic treatment with valproic acid. Neuropsychopharmacology 22:27–35

    Article  CAS  PubMed  Google Scholar 

  • Seo JH, Rah JC, Choi SH, Shin JK, Min K, Kim HS, Park CH, Kim S, Kim EM, Lee SH, Lee S, Suh SW, Suh YH (2002) Alpha-synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway. FASEB J 16:1826–1828

    CAS  PubMed  Google Scholar 

  • Sherer TB, Kim JH, Betarbet R, Greenamyre JT (2003a) Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp Neurol 179:9–16

    Article  CAS  PubMed  Google Scholar 

  • Sherer TB, Betarbet R, Kim JH, Greenamyre JT (2003b) Selective microglial activation in the rat rotenone model of Parkinson’s disease. Neurosci Lett 341:87–90

    Article  CAS  PubMed  Google Scholar 

  • Sinn DI, Kim SJ, Chu K, Jung KH, Lee ST, Song EC, Kim JM, Park DK, Kun Lee S, Kim M, Roh JK (2007) Valproic acid- mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis 26:464–472

    Article  CAS  PubMed  Google Scholar 

  • White LD, Barone S Jr (2001) Qualitative and quantitative estimates of apoptosis from birth to senescence in the rat brain. Cell Death Differ 8:345–356

    Article  CAS  PubMed  Google Scholar 

  • Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H (2004) Overexpression of alpha-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of alpha-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson’s disease. J Neurochem 91:451–461

    Article  CAS  PubMed  Google Scholar 

  • Yoshida M (2007) Multiple system atrophy: alpha-synuclein and neuronal degeneration. Neuropathology 27:484–493

    Article  PubMed  Google Scholar 

  • Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, Uéda K, Chan P (2007) Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience 145:539–555

    Article  CAS  PubMed  Google Scholar 

  • Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Muñoz DG, de Yebenes JG (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The present work was supported by grants of the Italian Ministry for Universities and Research to A.C. (FIRB funding scheme) and M.V. (PRIN funding scheme). The authors wish to thank Dr. Gabriele Grossi of the Laboratorio Centralizzato, Policlinico S.Orsola-Malpighi, Bologna, for his assistance with dopamine measurements. The skilful technical assistance of Miss Monia Bentivogli is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Biology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy

    Barbara Monti, Valentina Gatta, Francesca Piretti, Marco Virgili & Antonio Contestabile

  2. Laboratorio Centralizzato, Policlinico S.Orsola-Malpighi, 40126, Bologna, Italy

    Simonetta S. Raffaelli

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  1. Barbara Monti
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  2. Valentina Gatta
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  3. Francesca Piretti
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  5. Marco Virgili
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  6. Antonio Contestabile
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Correspondence to Antonio Contestabile.

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Monti, B., Gatta, V., Piretti, F. et al. Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein. Neurotox Res 17, 130–141 (2010). https://doi.org/10.1007/s12640-009-9090-5

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