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Progressive Dopaminergic Degeneration in the Chronic MPTPp Mouse Model of Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is characterized by a progressive degeneration of dopamine (DA) neurons and gradual worsening of motor symptoms. The investigation of progressive degenerative mechanisms and potential neuroprotective strategies relies on experimental models of the chronic neuropathology observed in human. The present study investigated the progressive nature of neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp) chronic mouse model of PD. MPTP (25 mg/kg) plus probenecid (250 mg/kg) were administered twice a week for 5 weeks. We evaluated behavioral deficits (olfactory and motor impairment), neurodegeneration (loss of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, SNc), biochemical markers of functional impairment in the caudate-putamen (CPu) (striatal enkephalin mRNA, DA and DOPAC levels), and glial reactivity (CD11b and GFAP immunoreactivity in the SNc and CPu) at progressive time-points (after 1, 3, 7, and 10 administrations of MPTPp). Olfactory dysfunction already appeared after the 1st MPTPp injection, whereas motor dysfunction appeared after the 3rd and worsened upon subsequent administrations. Moreover, starting after three MPTPp injections, we observed a gradual decline of TH-positive cells in the SNc, and a gradual raise of enkephalin mRNA in the CPu. Striatal DA levels reduction was not different among all time-points evaluated, whereas DOPAC levels were similarly reduced after 1–7 MPTP injections, but were further decreased after the 10th injection. Reactive microglia and astroglia were observed in both the SNc and CPu from the 1st MPTPp administration. In the SNc, gliosis displayed a gradual increase over the treatment. After 2 months, TH, DA, DOPAC, and reactive glia in the SNc were still altered in MPTPp-treated mice as compared to controls. By showing a progressive development of behavioral deficits and nigral neurodegeneration, together with impairment of biochemical parameters and gradual increase of glial response, results suggest that the chronic MPTPp protocol is a model of progressive PD, which may be suitable to investigate chronic pathological processes and neuroprotective strategies in PD.

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References

  • Alvarez-Fischer D, Guerreiro S, Hunot S, Saurini F, Marien M, Sokoloff P, Hirsch EC, Hartmann A, Michel PP (2008) Modelling Parkinson-like neurodegeneration via osmotic minipump delivery of MPTP and probenecid. J Neurochem 107:701–711

    Article  PubMed  CAS  Google Scholar 

  • Anglade P, Mouatt-Prigent A, Agid Y, Hirsch E (1996) Synaptic plasticity in the caudate nucleus of patients with Parkinson’s disease. Neurodegeneration 5:121–128

    Article  PubMed  CAS  Google Scholar 

  • Araki T, Mikami T, Tanji H, Matsubara M, Imai Y, Mizugaki M, Itoyama Y (2001) Biochemical and immunohistological changes in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse. Eur J Pharm Sci 12:231–238

    Article  PubMed  CAS  Google Scholar 

  • Barcia C, Fernández Barreiro A, Poza M, Herrero MT (2003) Parkinson’s disease and inflammatory changes. Neurotox Res 5:411–418

    PubMed  Google Scholar 

  • Barcia C, Sánchez Bahillo A, Fernández-Villalba E, Bautista V, Poza Y, Poza M, Fernández-Barreiro A, Hirsch EC, Herrero MT (2004) Evidence of active microglia in substantia nigra pars compacta of parkinsonian monkeys 1 year after MPTP exposure. Glia 46:402–419

    Article  PubMed  Google Scholar 

  • Berendse HW, Booij J, Francot CM, Bergmans PL, Hijman R, Stoof JC, Wolters EC (2001) Subclinical dopaminergic dysfunction in asymptomatic Parkinson’s disease patients’ relatives with a decreased sense of smell. Ann Neurol 50:34–41

    Article  PubMed  CAS  Google Scholar 

  • Bezard E, Jaber M, Gonon F, Boireau A, Bloch B, Gross CE (2000a) Adaptive changes in the nigrostriatal pathway in response to increased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration in the mouse. Eur J Neurosci 12:2892–2900

    Article  PubMed  CAS  Google Scholar 

  • Bezard E, Dovero S, Imbert C, Boraud T, Gross CE (2000b) Spontaneous long-term compensatory dopaminergic sprouting in MPTP-treated mice. Synapse 38:363–368

    Article  PubMed  CAS  Google Scholar 

  • Blanchard V, Chritin M, Vyas S, Savasta M, Feuerstein C, Agid Y, Javoy-Agid F, Raisman-Vozari R (1995) Long-term induction of tyrosine hydroxylase expression: compensatory response to partial degeneration of the dopaminergic nigrostriatal system in the rat brain. J Neurochem 64:1669–1679

    PubMed  CAS  Google Scholar 

  • Blandini F, Armentero MT, Martignoni E (2008) The 6-hydroxydopamine model: news from the past. Parkinsonism Relat Disord 2:S124–S129

    Article  Google Scholar 

  • Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  • Carta AR, Tronci E, Pinna A, Morelli M (2005) Different responsiveness of striatonigral and striatopallidal neurons to l-DOPA after a subchronic intermittent l-DOPA treatment. Eur J Neurosci 21:1196–1204

    Article  PubMed  CAS  Google Scholar 

  • Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, Bates GP, Dunnett SB, Morton AJ (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. J Neurosci 19:3248–3257

    PubMed  CAS  Google Scholar 

  • Chase TN, Oh JD (2000) Striatal dopamine- and glutamate-mediated dysregulation in experimental parkinsonism. Trends Neurosci 23:S86–S91

    Article  PubMed  CAS  Google Scholar 

  • Chesselet MF, Fleming S, Mortazavi F, Meurers B (2008) Strengths and limitations of genetic mouse models of Parkinson’s disease. Parkinsonism Relat Disord 2:S84–S87

    Article  Google Scholar 

  • Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF (1997) Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol 79:163–175

    Article  PubMed  CAS  Google Scholar 

  • Dentresangle C, Le Cavorsin M, Savasta M, Leviel V (2001) Increased extracellular DA and normal evoked DA release in the rat striatum after a partial lesion of the substantia nigra. Brain Res 893:178–185

    Article  PubMed  CAS  Google Scholar 

  • Dervan AG, Meshul CK, Beales M, McBean GJ, Moore C, Totterdell S, Snyder AK, Meredith GE (2004) Astroglial plasticity and glutamate function in a chronic mouse model of Parkinson’s disease. Exp Neurol 190:145–156

    Article  PubMed  CAS  Google Scholar 

  • Dluzen DE, McDermott JL, Anderson LI, Kucera J, Joyce JN, Osredkar T, Walro JM (2004) Age-related changes in nigrostriatal dopaminergic function are accentuated in ± brain-derived neurotrophic factor mice. Neuroscience 128:201–208

    Article  PubMed  CAS  Google Scholar 

  • Drucker-Colín R, García-Hernández F (1991) A new motor test sensitive to aging and dopaminergic function. J Neurosci Methods 39:153–161

    Article  PubMed  Google Scholar 

  • Elsworth JD, Taylor JR, Sladek JR Jr, Collier TJ, Redmond DE Jr, Roth RH (2000) Striatal dopaminergic correlates of stable parkinsonism and degree of recovery in old-world primates 1 year after MPTP treatment. Neuroscience 95:399–408

    Article  PubMed  CAS  Google Scholar 

  • Fernagut PO, Chalon S, Diguet E, Guilloteau D, Tison F, Jaber M (2003) Motor behaviour deficits and their histopathological and functional correlates in the nigrostriatal system of dopamine transporter knockout mice. Neuroscience 116:1123–1130

    Article  PubMed  CAS  Google Scholar 

  • Fleming SM, Salcedo J, Fernagut PO, Rockenstein E, Masliah E, Levine MS, Chesselet MF (2004) Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alphasynuclein. J Neurosci 24:9434–9440

    Article  PubMed  CAS  Google Scholar 

  • Fornai F, Schlüter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, Südhof TC (2005) Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci USA 102:3413–3418

    Article  PubMed  CAS  Google Scholar 

  • Forno LS, DeLanney LE, Irwin I, Di Monte D, Langston JW (1992) Astrocytes and Parkinson’s disease. Prog Brain Res 94:429–436

    Article  PubMed  CAS  Google Scholar 

  • Gerfen CR (2003) D1 dopamine receptor supersensitivity in the dopamine-depleted striatum animal model of Parkinson’s disease. Neuroscientist 9:455–462

    Article  PubMed  CAS  Google Scholar 

  • Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ Jr, Sibley DR (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429–1432

    Article  PubMed  CAS  Google Scholar 

  • Haehner A, Hummel T, Hummel C, Sommer U, Junghanns S, Reichmann H (2007) Olfactory loss may be a first sign of idiopathic Parkinson’s disease. Mov Disord 22:839–842

    Article  PubMed  Google Scholar 

  • Hald A, Lotharius J (2005) Oxidative stress and inflammation in Parkinson’s disease: is there a causal link? Exp Neurol 193:279–290 (Review)

    Article  PubMed  CAS  Google Scholar 

  • Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:214–228

    PubMed  CAS  Google Scholar 

  • Jackson-Lewis V, Jakowec M, Burke RE, Przedborski S (1995) Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration 4:257–269

    Article  PubMed  CAS  Google Scholar 

  • Jenner P (2008) Functional models of Parkinson’s disease: a valuable tool in the development of novel therapies. Ann Neurol 2:S16–S29

    Google Scholar 

  • Kohutnicka M, Lewandowska E, Kurkowska-Jastrzebska I, Członkowski A, Członkowska A (1998) Microglial and astrocytic involvement in a murine model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunopharmacology 39:167–180

    Article  PubMed  CAS  Google Scholar 

  • Kurkowska-Jastrzebska I, Wrońska A, Kohutnicka M, Członkowski A, Członkowska A (1999) The inflammatory reaction following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication in mouse. Exp Neurol 156:50–61

    Article  PubMed  CAS  Google Scholar 

  • Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5:1403–1409

    Article  PubMed  CAS  Google Scholar 

  • Linder JC, Klemfuss H, Groves PM (1987) Acute ultrastructural and behavioral effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Neurosci Lett 82:221–226

    Article  PubMed  CAS  Google Scholar 

  • Manning-Bog AB, Langston JW (2007) Model fusion, the next phase in developing animal models for Parkinson’s disease. Neurotox Res 11:219–240 Review

    Article  PubMed  CAS  Google Scholar 

  • Matsuura K, Kabuto H, Makino H, Ogawa N (1997) Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion. J Neurosci Methods 73:45–48

    Article  PubMed  CAS  Google Scholar 

  • McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23:474–483

    Article  PubMed  Google Scholar 

  • McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291

    PubMed  CAS  Google Scholar 

  • Meredith GE, Kang UJ (2006) Behavioral models of Parkinson’s disease in rodents: a new look at an old problem. Mov Disord 21:1595–1606 Review

    Article  PubMed  Google Scholar 

  • Meredith GE, Totterdell S, Petroske E, Santa Cruz K, Callison RC Jr, Lau YS (2002) Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson’s disease. Brain Res 22:156–165

    Article  Google Scholar 

  • Meredith GE, Dervan AG, Totterdell S (2005) Activated microglia persist in the substantia nigra of a chronic MPTP mouse model of Parkinson’s disease. In: Bolam JP, Ingham, Magill PJ (eds) The basal ganglia VIII. Springer Science, Singapore, pp 341–347

    Chapter  Google Scholar 

  • Meredith GE, Totterdell S, Potashkin JA, Surmeier DJ (2008) Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol. Parkinsonism Relat Disord 2:S112–S115

    Article  Google Scholar 

  • Mitra N, Mohanakumar KP, Ganguly DK (1992) Dissociation of serotoninergic and dopaminergic components in acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Brain Res Bull 28:355–364

    Article  PubMed  CAS  Google Scholar 

  • Mitsumoto Y, Watanabe A, Mori A, Koga N (1998) Spontaneous regeneration of nigrostriatal dopaminergic neurons in MPTP-treated C57BL/6 mice. Biochem Biophys Res Commun 248:660–663

    Article  PubMed  CAS  Google Scholar 

  • Novikova L, Garris BL, Garris DR, Lau YS (2006) Early signs of neuronal apoptosis in the substantia nigra pars compacta of the progressive neurodegenerative mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid model of Parkinson’s disease. Neuroscience 140:67–76

    Article  PubMed  CAS  Google Scholar 

  • Ogawa N, Hirose Y, Ohara S, Ono T, Watanabe Y (1985) A simple quantitative bradykinesia test in MPTP-treated mice. Res Commun Chem Pathol Pharmacol 50:435–441

    PubMed  CAS  Google Scholar 

  • Ogawa N, Mizukawa K, Hirose Y, Kajita S, Ohara S, Watanabe Y (1987) MPTP-induced parkinsonian model in mice: biochemistry, pharmacology and behavior. Eur Neurol 1:16–23

    Article  Google Scholar 

  • Olanow CW (2007) The pathogenesis of cell death in Parkinson’s disease. Mov Disord 17:S335–S342

    Article  Google Scholar 

  • Olanow CW, Kieburtz K, Schapira AH (2008) Why have we failed to achieve neuroprotection in Parkinson’s disease? Ann Neurol 2:S101–S110

    Google Scholar 

  • Paxinos G, Franklin KBJ (eds) (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San Diego

    Google Scholar 

  • Perez XA, Parameswaran N, Huang LZ, O’Leary KT, Quik M (2008) Pre-synaptic dopaminergic compensation after moderate nigrostriatal damage in non-human primates. J Neurochem 105:1861–1872

    Article  PubMed  CAS  Google Scholar 

  • Petroske E, Meredith GE, Callen S, Totterdell S, Lau YS (2001) Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 106:589–601

    Article  PubMed  CAS  Google Scholar 

  • Quinn LP, Perren MJ, Brackenborough KT, Woodhams PL, Vidgeon-Hart M, Chapman H, Pangalos MN, Upton N, Virley DJ (2007) A beam-walking apparatus to assess behavioural impairments in MPTP-treated mice: pharmacological validation with R-(−)-deprenyl. J Neurosci Methods 164:43–49

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Mocsary Z, Camp DM, Whishaw IQ (1994) Time course of recovery of extracellular dopamine following partial damage to the nigrostriatal dopamine system. J Neurosci 14:2687–2696

    PubMed  CAS  Google Scholar 

  • Rousselet E, Joubert C, Callebert J, Parain K, Tremblay L, Orieux G, Launay JM, Cohen-Salmon C, Hirsch EC (2003) Behavioral changes are not directly related to striatal monoamine levels, number of nigral neurons, or dose of parkinsonian toxin MPTP in mice. Neurobiol Dis 14:218–228

    Article  PubMed  CAS  Google Scholar 

  • Schintu N, Frau L, Ibba M, Caboni P, Garau A, Carboni E, Carta AR (2009) PPAR-gamma mediated neuroprotection in a chronic mouse model of Parkinson’s disease. Eur J Neurosci 29:954–963

    Article  PubMed  Google Scholar 

  • Schneider B, Zufferey R, Aebischer P (2008) Viral vectors, animal models and new therapies for Parkinson’s disease. Parkinsonism Relat Disord 2:S169–S171

    Article  Google Scholar 

  • Sedelis M, Schwarting RK, Huston JP (2001) Behavioral phenotyping of the MPTP mouse model of Parkinson’s disease. Behav Brain Res 125:109–125

    Article  PubMed  CAS  Google Scholar 

  • Serradj N, Jamon M (2007) Age-related changes in the motricity of the inbred mice strains 129/sv, C57BL/6j. Behav Brain Res 177:80–89

    Article  PubMed  Google Scholar 

  • Smeyne RJ, Jackson-Lewis V (2005) The MPTP model of Parkinson’s disease. Brain Res Mol Brain Res 134:57–66

    Article  PubMed  CAS  Google Scholar 

  • Sofroniew MV (2005) Reactive astrocytes in neural repair and protection. Neuroscientist 11:400–407

    Article  PubMed  CAS  Google Scholar 

  • Sonsalla PK, Zeevalk GD, German DC (2008) Chronic intraventricular administration of 1-methyl-4-phenylpyridinium as a progressive model of Parkinson’s disease. Parkinsonism Relat Disord 2:S116–S118

    Article  Google Scholar 

  • Tansey MG, McCoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 208:1–25

    Article  PubMed  CAS  Google Scholar 

  • Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771

    PubMed  CAS  Google Scholar 

  • Yazdani U, German DC, Liang CL, Manzino L, Sonsalla PK, Zeevalk GD (2006) Rat model of Parkinson’s disease: chronic central delivery of 1-methyl-4-phenylpyridinium (MPP+). Exp Neurol 200:172–183

    PubMed  CAS  Google Scholar 

  • Zhou C, Huang Y, Przedborski S (2008) Oxidative stress in Parkinson’s disease: a mechanism of pathogenic and therapeutic significance. Ann N Y Acad Sci 147:93–104

    Article  CAS  Google Scholar 

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  1. Department of Toxicology, University of Cagliari and National Institute for Neuroscience, via Ospedale 72, Cagliari, 09124, Italy

    Nicoletta Schintu, Lucia Frau, Marcello Ibba, Arianna Garau, Ezio Carboni & Anna R. Carta

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  1. Nicoletta Schintu
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  2. Lucia Frau
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  3. Marcello Ibba
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  4. Arianna Garau
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  5. Ezio Carboni
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  6. Anna R. Carta
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Correspondence to Anna R. Carta.

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Nicoletta Schintu and Lucia Frau equally contributed to the work.

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Schintu, N., Frau, L., Ibba, M. et al. Progressive Dopaminergic Degeneration in the Chronic MPTPp Mouse Model of Parkinson’s Disease. Neurotox Res 16, 127–139 (2009). https://doi.org/10.1007/s12640-009-9061-x

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