Metabolic Brain Disease

, Volume 24, Issue 2, pp 321–335 | Cite as

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

  • E. Lagrue
  • B. Abert
  • L. Nadal
  • L. Tabone
  • S. Bodard
  • F. Medja
  • A. Lombes
  • S. Chalon
  • P. Castelnau
Original Paper
First Online:
Received:
Accepted:

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.

Keywords

Basal ganglia Mitochondria MPTP Leigh syndrome Neuroprotection Mouse 

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

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Notes

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.

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • E. Lagrue
    • 1
    • 2
    • 3
  • B. Abert
    • 1
    • 3
  • L. Nadal
    • 1
    • 2
  • L. Tabone
    • 1
  • S. Bodard
    • 1
  • F. Medja
    • 4
  • A. Lombes
    • 4
  • S. Chalon
    • 1
    • 2
  • P. Castelnau
    • 1
    • 2
    • 3
    • 5
  1. 1.Unité Imagerie et CerveauToursFrance
  2. 2.Université François-RabelaisToursFrance
  3. 3.Neuropediatric, Pôle de Pédiatrie Medicale, Hôpital Clocheville, CHRU ToursToursFrance
  4. 4.INSERM U582, AP-HP, GHU Pitié-SalpêtrièreParisFrance
  5. 5.Neuropédiatrie et Inserm U930, Centre de Competence pour les maladies mitochondriales, Université François RabelaisLaboratoire de Biophysique Médicale et Pharmaceutique37200 ToursFrance

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