Skip to main content

Advertisement

SpringerLink
Log in

MPTP intoxication in mice: a useful model of Leigh syndrome to study mitochondrial diseases in childhood

  • Original Paper
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

The basal ganglia, which are interconnected in the striato-nigral dopaminergic network, are affected in several childhood diseases including Leigh syndrome (LS). LS is the most common mitochondrial disorder affecting children and usually arise from inhibition of the respiratory chain. This vulnerability is attributed to a particular susceptibility to energetic stress, with mitochondrial inhibition as a common pathogenic pathway. In this study we developed a LS model for neuroprotection trials in mice by using the complex I inhibitor MPTP. We first verified that MPTP significantly inhibits the mitochondrial complex I in the brain (p = 0.018). This model also reproduced the biochemical and pathological features of LS: MPTP increased plasmatic lactate levels (p = 0.023) and triggered basal ganglia degeneration, as evaluated through dopamine transporter (DAT) autoradiography, tyrosine hydroxylase (TH) immunohistochemistry, and dopamine dosage. Striatal DAT levels were markedly decreased after MPTP treatment (p = 0.003). TH immunoreactivity was reduced in the striatum and substantia nigra (p = 0.005), and striatal dopamine was significantly reduced (p < 0.01). Taken together, these results confirm that acute MPTP intoxication in young mice provides a reproducible pharmacological paradigm of LS, thus opening new avenues for neuroprotection research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AU:

arbitrary unit

BSA:

bovine serum albumin

CSF:

cerebrospinal fluid

DA:

dopamine

DAT:

dopamine transporter

ip:

intraperitoneal

LS:

Leigh syndrome

MAO-B:

monoamine oxidase B

MPP +:

N-methyl-4-phenylpyridinium

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MRI:

magnetic resonance imaging

MRS:

magnetic resonance spectroscopy

PET:

positron emission tomography

RT:

room temperature

SNpc:

substantia nigra pars compacta

TH:

tyrosine hydroxylase

vs:

versus

References

  • Beal MF (2000) Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci. 23:298–304

    Article  PubMed  CAS  Google Scholar 

  • Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR (2002) Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 59:1406–1411

    Article  PubMed  CAS  Google Scholar 

  • Böhm M, Pronicka E, Karczmarewicz E, Pronicki M, Piekutowska-Abramczuk D, Sykut-Cegielska J, Mierzewska H, Hansikova H, Vesela K, Tesarova M, Houstkova H, Houstek J, Zeman J (2006) Retrospective, multicentric study of 180 children with cytochrome C oxidase deficiency. Pediatr Res 59:21–26

    Article  PubMed  Google Scholar 

  • Boska MD, Hasan KM, Kibuule D, Banerjee R, McIntyre E, Nelson JA, Hahn T, Gendelman HE, Mosley RL (2007) Quantitative diffusion tensor imaging detects dopaminergic neuronal degeneration in a murine model of Parkinson’s disease. Neurobiol Dis 26:590–596

    Article  PubMed  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Brown GK, Squier MV (1996) Neuropathology and pathogenesis of mitochondrial diseases. J Inherit Metab Dis 19:553–572

    Article  PubMed  CAS  Google Scholar 

  • Brownell AL, Jenkins BG, Elmaleh DR, Deacon TW, Spealman RD, Isacson O (1998) Combined PET/MRS brain studies show dynamic and long term physiological changes in a primate model of Parkinson’s disease. Nat Med 4:1308–1312

    Article  PubMed  CAS  Google Scholar 

  • Byrne E (2002) Does mitochondrial respiratory chain dysfunction have a role in common neurodegenerative disorders? J Clin Neurosci 9:497–501

    Article  PubMed  CAS  Google Scholar 

  • Castro-Gago M, Blanco-Barca MO, Campos-Gonsalez Y, Arenas-Barbero J, Pintos-Martinez E, Eiris-Punal J (2006) Epidemiology of pediatric mitochondrial respiratory chain in northwest Spain. J Pediatr Neurol 34:204–211

    Article  Google Scholar 

  • Chalon S, Garreau L, Emond P, Zimmer L, Vilar MP, Besnard JC, Guilloteau D (1999) Pharmacological characterization of (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta(4′-methylphenyl) nortropane as a selective and potent inhibitor of the neuronal dopamine transporter. J Pharmacol Exp Ther 291:648–654

    PubMed  CAS  Google Scholar 

  • Cleeter MWJ, Cooper JM, Schapira AHV (2001) Nitric oxide enhances MPP + inhibition of complex I. FEBS Lett 504:50–52

    Article  PubMed  CAS  Google Scholar 

  • Cleren C, Yang L, Lorenzo B, Calingasan NY, Schomer A, Sireci A, Wille EJ, Flint Beal M (2008) Therapeutic effects of coenzyme Q10 and reduced coenzyme Q10 in the MPTP model of Parkinsonism. J Neurochem 104:1613–1621

    Article  PubMed  CAS  Google Scholar 

  • Crocker SJ, Liston P, Anisman H, Lee CJ, Smith PD, Earl N, Thompson CS, Park DS, Korneluk RG, Robertson GS (2003) Attenuation of MPTP-induced neurotoxicity and behavioural impairment in NSE-XIAP transgenic mice. Neurobiol Dis 12:150–161

    Article  PubMed  CAS  Google Scholar 

  • Debray FG, Lambert M, Chevallier I, Decarie JC, Shoubridge EA, Robinson BH, Mitchell GA (2007) Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 119:722–733

    Article  PubMed  Google Scholar 

  • Dietz GP, Stockhausen KV, Dietz B, Falkenburger BH, Valbuena P, Opazo F, Lingor P, Meuer K, Weishaupt H, Schulz JB, Bähr M (2008) Membrane-permeable Bcl-xL prevents MPTP-induced dopaminergic neuronal loss in the substantia nigra. J Neurochem 104:757–765

    PubMed  CAS  Google Scholar 

  • Di Filippo M, Picconi B, Costa C, Bagetta V, Tantucci M, Parnetti L, Calabresi P (2006) Pathways of neurodegeneration and experimental models of basal ganglia disorders: downstream effects of mitochondrial inhibition. Eur J Pharmacol 1:65–72

    Article  CAS  Google Scholar 

  • Geng X, Tian X, Tu P, Pu X (2007) Neuroprotective effects of echinacoside in the mouse model of MPTP model of Parkinson’s disease. Eur J Pharmacol 564:66–74

    Article  PubMed  CAS  Google Scholar 

  • Gluck MR, Krueger MJ, Ramsay RR, Sablin SO, Singer TP, Nicklas WJ (1994) Characterization of the inhibitory mechanism of 1-methyl-4-phenylpyridinium and 4-phenylpyridine analogs in inner membrane preparations. J Biol Chem 269:3167–3174

    PubMed  CAS  Google Scholar 

  • Hamill CE, Caudle WM, Richardson JR, Yuan H, Pennell KD, Greene JG, Miller GW, Traynelis SF (2007) Exacerbation of dopaminergic terminal damage in a mouse model of Parkinson’s disease by the G-protein-coupled receptor-activated receptor 1. Mol Pharmacol 73:653–664

    Article  CAS  Google Scholar 

  • Hartig MB, Hortnagel K, Garavaglia B, Zorzi G, Kmiec T, Klopstock T, Rostasy K, Svetel M, Kostic VS, Schuelke M, Botz E, Weindl A, Novakovic I, Nardocci N, Prokisch H, Meitinger T (2006) Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann Neurol 59:248–256

    Article  PubMed  CAS  Google Scholar 

  • Himeda T, Kadoguchi N, Kamiyama Y, Kato H, Maegawa H, Araki T (2006) Neuroprotective effect of arundic acid, an astrocyte modulating agent, in mouse brain against MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) neurotoxicity. Neuropharmacology 50:329–344

    Article  PubMed  CAS  Google Scholar 

  • Hirata Y, Nagatsu T (2005) Rotenone and CCCP inhibit tyrosine hydroxylation in rat striatal tissue slices. Toxicology 216:9–14

    Article  PubMed  CAS  Google Scholar 

  • Höglinger GU, Carrard G, Michel PP, Medja F, Lombès A, Ruberg M, Friguet B, Hirsch EC (2003) Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson’s disease. J Neurochem 86:1297–1307

    PubMed  Google Scholar 

  • Klawitter V, Morales P, Bustamante D, Gomez-Urquijo S, Hökfelt T, Herrera-Marschitz M (2007) Plasticity of basal ganglia neurocircuitries following perinatal asphyxia: effect of nicotinamide. Exp Brain Res 180:139–152

    Article  PubMed  CAS  Google Scholar 

  • Koga K, Mori A, Ohashi S, Kurihara N, Kitagawa H, Ishikawa M, Mitsumoto Y, Nakai M (2006) H MRS identifies lactate rise in the striatum of MPTP-treated C57BL/6 mice. Eur J Neurosci 23:1077–1081

    Article  PubMed  Google Scholar 

  • Krägeloh-Mann I, Grodd W, Schöning M, Marquard K, Nägele T, Ruitenbeek W (1993) Proton spectroscopy in five patients with Leigh’s disease and mitochondrial enzyme deficiency. Dev Med Child Neurol 35:769–776

    Article  PubMed  Google Scholar 

  • Lagrue E, Chalon S, Bodard S, Saliba E, Gressens P, Castelnau P (2007) Lamotrigine is neuroprotective in the energy deficiency model of MPTP intoxicated mice. Pediatr Res 62:14–19

    Article  PubMed  CAS  Google Scholar 

  • Lebon S, Minai L, Chretien D, Corcos J, Serre V, Kadhom N, Steffann J, Pauchard JY, Munnich A, Bonnefont JP, Rotig A (2007) A novel mutation of the NDUFS7 gene leads to activation of a cryptic exon and impaired assembly of mitochondrial complex I in a patient with Leigh syndrome. Mol Genet Metab 27:104–108

    Article  CAS  Google Scholar 

  • Leng A, Feldon J, Ferger B (2003) Rotenone increases glutamate-induced dopamine release but does not affect hydroxyl-free radical formation in rat striatum. Synapse 50:240–250

    Article  PubMed  CAS  Google Scholar 

  • Liang LP, Huang J, Fulton R, Day BJ, Patel M (2007) An orally active catalytic metalloporphyrin protects against 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine in vivo. J Neurosci 27:4326–4333

    Article  PubMed  CAS  Google Scholar 

  • Linder JC, Young SJ, Groves PM (1995) Electron microscopic evidence for neurotoxicity in the basal ganglia. Neurochem Int 26:195–202

    Article  PubMed  CAS  Google Scholar 

  • Liss B, Roeper J (2002) Correlating function and gene expression of individual basal ganglia neurons. Trends Neurosci 27:475–481

    Article  CAS  Google Scholar 

  • Malfatti E, Bugiani M, Invernizzi F, de Souza CF, Farina L, Carrara F, Lamantea E, Antozzi C, Confalonieri P, Sanseverino MT, Giugliani R, Uziel G, Zeviani M (2007) Novel mutations of ND genes in complex I deficiency associated with mitochondrial encephalopathy. Brain 130:1894–1904

    Article  PubMed  Google Scholar 

  • Mandemakers W, Morais VA, De Strooper B (2007) A cell biological perspective on mitochondrial dysfunction in Parkinson’s disease and other neurodegenerative diseases. J Cell Sci 15:1707–1716

    Article  CAS  Google Scholar 

  • Marti MJ, James CJ, Oo TF, Kelly WJ, Burke RE (1997) Early developmental destruction of terminals in the striatal target induces apoptosis in dopamine neurons of the substantia nigra. J Neurosci 17:2030–2039

    PubMed  CAS  Google Scholar 

  • Mercier, S., Josselin de Wasch, M., Labarthe, F., Jardel, C., Lombès, A., Munnich, A., Toutain, A., Nivet, H., Saliba, E., Chantepie, A., Castelnau P (2009) Clinical variability and diagnosis steps in childhood mitochondrial disease. Arch Ped (in press)

  • Miletich RS, Bankiewicz KS, Quarantelli M, Plunkett RJ, Frank J, Di Chiro G (1994) MRI detects acute degeneration of the nigrostriatal dopamine system after MPTP exposure in hemiparkinsonian monkeys. Ann Neurol 35:689–697

    Article  PubMed  CAS  Google Scholar 

  • Murphy MP, Krueger MJ, Sablin SO, Ramsay RR, Singer TP (1995) Inhibition of complex I by hydrophobic analogues of N-methyl-4-phenylpyridinium (MPP+) and the use of an ion-selective electrode to measure their accumulation by mitochondria and electron-transport particles. Biochem J 306:359–365

    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 

  • Oida Y, Kitaichi K, Nakayama H, Ito Y, Fujimoto Y, Shimazawa M, Nagai H, Hara H (2006) Rifampicine attenuates the MPTP-induced neurotoxicity in mouse brain. Brain Res 1082:196–204

    Article  PubMed  CAS  Google Scholar 

  • Okun JG, Horster F, Farkas LM, Feyh P, Hinz A, Sauer S, Hoffmann GF, Unsicker K, Mayatepek E, Kolker S (2002) Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle and synergistically acting excitotoxicity. J Biol Chem 26:14674–14680

    Google Scholar 

  • OMIM (Online Mendelian Inheritance in Man). Johns Hopkins University, Baltimore, MD. #256000; 08/06/2007. Available at: http://www.ncbi.nlm.nih.gov/omim. Accessed June 1, 2008.

  • Paxinos G, Franklin KB (2003) The mouse brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  • Petzer JP, Bergh JJ, Mienie LJ, Castagnoli N, Van Der Schyf CJ (2000) Metabolic defects caused by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and by HPTP (the tetrahydropyridinyl analog of haloperidol) in rats. Life Sci 66:1949–1954

    Article  PubMed  CAS  Google Scholar 

  • Petzinger GM, Walsh JP, Akopian G, Hogg E, Abernathy A, Arevalo P, Turnquist P, Vuckovic M, Fisher BE, Togasaki DM, Jakowec MW (2007) Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-lesioned model of basal ganglia injury. J Neurosci 27:5291–5300

    Article  PubMed  CAS  Google Scholar 

  • Piao YS, Tang GC, Yang H, Lu DH (2006) Clinico-neuropathological study of a Chinese case of familial adult Leigh syndrome. Neuropathology 26:218–221

    Article  PubMed  Google Scholar 

  • Podell M, Hadjiconstantinou M, Smith MA, Neff NH (2003) Proton magnetic resonance imaging and spectroscopy identify metabolic changes in the striatum in the MPTP feline model of parkinsonism. Exp Neurol 179:159–166

    Article  PubMed  CAS  Google Scholar 

  • Przedborski S, Jackson-Lewis V, Djaldetti R, Liberatore G, Vila M, Vukosavic S, Almer G (2000) The parkinsonian toxin MPTP: action and mechanism. Restor Neurol Neurosci 16:135–142

    PubMed  CAS  Google Scholar 

  • Qi X, Lewin AS, Sun L, Hauswirth WW, Guy J (2004) SOD2 gene transfer protects against optic neuropathy induced by deficiency of complex I. Ann Neurol 56:182–191

    Article  PubMed  CAS  Google Scholar 

  • Ramachandiran S, Hansen JM, Jones DP, Richardson JR, Miller GW (2007) Divergent mechanisms of paraquat, MPP + and rotenone toxicity: oxidation of thioredoxin and caspase-3 activation. Toxicol Sci 95:163–171

    Article  PubMed  CAS  Google Scholar 

  • Rollema H, Skolnik M, D’Engelbronner J, Igarashi K, Usuki E, Castagnoli N (1994) MPP +-like neurotoxicity of a pyridinium metabolite derived from haloperidol: in vivo microdialysis and in vitro mitochondrial studies. J Pharmacol Exp Ther 268:380–387

    PubMed  CAS  Google Scholar 

  • Rutherford MA, Azzopardi D, Whitelaw A, Cowan F, Renowden S, Edwards AD, Thoresen M (2005) Mild hypothermia and the distribution of cerebral lesions in neonates with hypoxic-ischemic encephalopathy. Pediatrics 116:1001–1006

    Article  PubMed  Google Scholar 

  • Sas K, Robotka H, Toldi J, Vecsei L (2007) Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. J Neurol Sci 257:221–239

    Article  PubMed  CAS  Google Scholar 

  • Saura J, Richards JG, Mahy N (1994) Age-related changes on MAO in Bl/C57 mouse tissues: a quantitative radioautographic study. J Neural Transm Suppl 41:89–94

    PubMed  CAS  Google Scholar 

  • Schiff M, Miné M, Brivet M, Marsac C, Elmaleh-Bergés M, Evrard P, Ogier de Baulny H (2006) Leigh’s disease due to a new mutation in the PDHX gene. Ann Neurol 59:709–714

    Article  PubMed  CAS  Google Scholar 

  • Schmidt WJ, Alam M (2006) Controversies on new animal models of Parkinson’s disease pro and con: the rotenone model of Parkinson’s disease (PD). J Neural Trans Suppl 70:273–276

    CAS  Google Scholar 

  • Turmel H, Hartmann A, Parain K, Douhou A, Srinivasan A, Agid Y, Hirsch EC (2001) Caspase-3 activation in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine: (MPTP)-treated mice. Mov Disord 16:185–189

    Article  PubMed  CAS  Google Scholar 

  • Vyas I, Heikkila RE, Nicklas WJ (1986) Studies on the neurotoxicity of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine: inhibition of NAD-linked substrate oxidation by its metabolite, 1-methyl-4-phenylpyridinium. J Neurochem 46:1501–1507

    Article  PubMed  CAS  Google Scholar 

  • Wallace BA, Ashkan K, Heise CE, Foote KD, Torres N, Mitrofanis J, Benabid AL (2007) Survival of midbrain dopaminergic cells after lesion or deep brain stimulation of the subthalamic nucleus in MPTP-treated monkeys. Brain 130:2129–2145

    Article  PubMed  Google Scholar 

  • Wallace DC (2002) Animal models for mitochondrial disease. Methods Mol Biol 197:3–54

    PubMed  CAS  Google Scholar 

  • Watanabe Y, Kato H, Araki T (2008) Protective action of neuronal nitric oxide synthase inhibitor in the MPTP mouse model of Parkinson’s disease. Metab Brain Dis 23:51–69

    Article  PubMed  CAS  Google Scholar 

  • Yang YL, Sun F, Zhang Y, Qian N, Yuan Y, Wang ZX, Qi Y, Xiao JX, Wang XY, Qi ZY, Zhang YH, Jiang YW, Bao XH, Qin J, Wu XR (2006) Clinical and laboratory survey of 65 Chinese patients with Leigh syndrome. Chin Med J (Engl) 119:373–377

    CAS  Google Scholar 

  • Zhang Z, Zhang M, Ai Y, Avison C, Gash DM (1999) MPTP-Induced pallidal lesions in rhesus monkeys. Exp Neurol 155:140–149

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank M-C. Furon for technical assistance with animal experiments, and Z. Gulhan, M-P. Vilar, and L. Galineau for contributive support on HPLC measurements. The authors also thank F. Paillard for editing the manuscript.

This work was supported by a fellowship from the Association des Anciens Internes des Hôpitaux de Paris to E. Lagrue.

Author information

Authors and Affiliations

  1. Unité Imagerie et Cerveau, Inserm, U930, Tours, F-37000, France

    E. Lagrue, B. Abert, L. Nadal, L. Tabone, S. Bodard, S. Chalon & P. Castelnau

  2. Université François-Rabelais, Tours, F-37000, France

    E. Lagrue, L. Nadal, S. Chalon & P. Castelnau

  3. Neuropediatric, Pôle de Pédiatrie Medicale, Hôpital Clocheville, CHRU Tours, Tours, F-37000, France

    E. Lagrue, B. Abert & P. Castelnau

  4. INSERM U582, AP-HP, GHU Pitié-Salpêtrière, UPMC-Paris 6, Paris, F-75651, France

    F. Medja & A. Lombes

  5. Neuropédiatrie et Inserm U930, Centre de Competence pour les maladies mitochondriales, Université François Rabelais, Laboratoire de Biophysique Médicale et Pharmaceutique, 31 Avenue Monge, 37200 , Tours, France

    P. Castelnau

Authors
  1. E. Lagrue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Abert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Nadal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Tabone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Bodard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. Medja
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Lombes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S. Chalon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P. Castelnau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. Castelnau.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lagrue, E., Abert, B., Nadal, L. et al. MPTP intoxication in mice: a useful model of Leigh syndrome to study mitochondrial diseases in childhood. Metab Brain Dis 24, 321–335 (2009). https://doi.org/10.1007/s11011-009-9132-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-009-9132-y

Keywords

Search

Navigation