title: 6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson's disease: respirometric, histological, and behavioral analyses.
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.
authors.affiliation: Department of Stereotactic Neurosurgery, Otto-von-Guericke-Universität/Medizinische Fakultät, Leipziger Str. 44, 39120, Magdeburg, Germany, andreas.kupsch@med.ovgu.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kupsch
authors.forename: Werner
authors.initials: W
authors.lastname: Schmidt
authors.forename: Zemfira
authors.initials: Z
authors.lastname: Gizatullina
authors.forename: Grazyna
authors.initials: G
authors.lastname: Debska-Vielhaber
authors.forename: Jürgen
authors.initials: J
authors.lastname: Voges
authors.forename: Frank
authors.initials: F
authors.lastname: Striggow
authors.forename: Patricia
authors.initials: P
authors.lastname: Panther
authors.forename: Herbert
authors.initials: H
authors.lastname: Schwegler
authors.forename: Hans-Jochen
authors.initials: HJ
authors.lastname: Heinze
authors.forename: Stefan
authors.initials: S
authors.lastname: Vielhaber
authors.forename: Frank Norbert
authors.initials: FN
authors.lastname: Gellerich
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality; D007150:Immunohistochemistry; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase