6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson’s disease: respirometric, histological, and behavioral analyses
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.
KeywordsParkinson’s disease Respirometry 6-OHDA model Mitochondria complex 1 Dopamine Substantia nigra pars compacta Flux control coefficients
Mitochondrial membrane potential
Flux control coefficient
Ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid
Uninhibited respiration rate
Median forebrain bundle
Respiratory control ratio
Relative complex I-dependent respiratory rate
Reactive oxygen species
Substantia nigra pars compacta
Tyrosine hydroxylase immunoreactive
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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