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Journal of Neural Transmission

, Volume 121, Issue 10, pp 1245–1257 | Cite as

6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson’s disease: respirometric, histological, and behavioral analyses

  • Andreas KupschEmail author
  • Werner Schmidt
  • Zemfira Gizatullina
  • Grazyna Debska-Vielhaber
  • Jürgen Voges
  • Frank Striggow
  • Patricia Panther
  • Herbert Schwegler
  • Hans-Jochen Heinze
  • Stefan Vielhaber
  • Frank Norbert GellerichEmail author
Neurology and Preclinical Neurological Studies - Original Article

Abstract

Mitochondrial defects have been shown to be associated with the pathogenesis of Parkinson’s disease (PD). Yet, experience in PD research linking mitochondrial dysfunction, e.g., deregulation of oxidative phosphorylation, with neuronal degeneration and behavioral changes is rather limited. Using the 6-hydroxydopamine (6-OHDA) rat model of PD, we have investigated the potential role of mitochondria in dopaminergic neuronal cell death in the substantia nigra pars compacta by high-resolution respirometry. Mitochondrial function was correlated with the time course of disease-related motor behavior asymmetry and dopaminergic neuronal cell loss, respectively. Unilateral 6-OHDA injections (>2.5 μg/2 μl) into the median forebrain bundle induced an impairment of oxidative phosphorylation due to a decrease in complex I activity. This was indicated by increased flux control coefficient. During the period of days 2–21, a progressive decrease in respiratory control ratio of up to −58 % was observed in the lesioned compared to the non-lesioned substantia nigra of the same animals. This decrease was associated with a marked uncoupling of oxidative phosphorylation. Mitochondrial dysfunction, motor behavior asymmetry, and dopaminergic neuronal cell loss correlated with dosage (1.25–5 μg/2 μl). We conclude that high-resolution respirometry may allow the detection of distinct mitochondrial dysfunction as a suitable surrogate marker for the preclinical assessment of potential neuroprotective strategies in the 6-OHDA model of PD.

Keywords

Parkinson’s disease Respirometry 6-OHDA model Mitochondria complex 1 Dopamine Substantia nigra pars compacta Flux control coefficients 

Abbreviations

ΔΨ

Mitochondrial membrane potential

AdN

Adenine nucleotide

C0

Flux control coefficient

Cat

Carboxyatractyloside

CP

Pearson’s correlation

E

Enzyme activity

EGTA

Ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid

G-3-P

Glycero-3-phosphate

G-3-PDH

G-3-P-dehydrogenase

MPTP

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

J

Uninhibited respiration rate

MFB

Median forebrain bundle

MOPS

3-(N-morpholino)propanesulfonic acid

mtDNA

Mitochondrial DNA

6-OHDA

6-Hydroxydopamine

PBS

Phosphate-buffered saline

PD

Parkinson’s disease

RCR

Respiratory control ratio

RCIR

Relative complex I-dependent respiratory rate

ROS

Reactive oxygen species

SN

Substantia nigra

SNPC

Substantia nigra pars compacta

TH

Tyrosine hydroxylase

TH-IR

Tyrosine hydroxylase immunoreactive

Notes

Acknowledgments

F.S. was supported by the Federal Ministry for Education and Research (BMBF Grant Number 03IS2211I/ProNetT3). A.K. was in part supported by Deutsche Forschungsgemeinschaft KFO 247 (Deep brain stimulation, Berlin).

We would like to thank J. Hübner and N. Huß for their excellent technical assistance.

Conflict of interest

The authors reported no financial interests or potential conflicts of interest.

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Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Andreas Kupsch
    • 1
    • 2
    Email author
  • Werner Schmidt
    • 4
  • Zemfira Gizatullina
    • 3
  • Grazyna Debska-Vielhaber
    • 2
  • Jürgen Voges
    • 1
    • 3
  • Frank Striggow
    • 4
  • Patricia Panther
    • 1
  • Herbert Schwegler
    • 5
  • Hans-Jochen Heinze
    • 2
    • 3
  • Stefan Vielhaber
    • 2
  • Frank Norbert Gellerich
    • 2
    • 3
    Email author
  1. 1.Department of Stereotactic NeurosurgeryOtto-von-Guericke-Universität/Medizinische FakultätMagdeburgGermany
  2. 2.Department of NeurologyOtto-von-Guericke-Universität/Medizinische FakultätMagdeburgGermany
  3. 3.Department of Behavioral NeurologyLeibniz-Institute for NeurobiologyMagdeburgGermany
  4. 4.Laboratory of Neurodegeneration and Intervention StrategiesGerman Center for Neurodegenerative Diseases (DZNE)MagdeburgGermany
  5. 5.Institute of AnatomyOtto-von-Guericke-Universität/Medizinische FakultätMagdeburgGermany

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