Controversies on new animal models of Parkinson's disease pro and con: the rotenone model of Parkinson's disease (PD).
A general complex I deficit has been hypothesized to contribute to neurodegeneration in Parkinson's disease (PD) and all toxins used to destroy dopaminergic neurons are complex I inhibitors. With MPTP or 6-OHdopamine, this hypothesis can not be tested since these toxins selectively accumulate in the dopaminergic neurons. However with rotenone, which penetrates all cells, the hypothesis can be tested. Thus, the proof of the hypothesis is whether or not rotenone-induced neurodegeneration mimics the degenerative processes underlying PD. Low doses of rotenone (1.5 or 2.5 mg/kg in oil i.p.) were administered to Sprague Dawley rats on a daily basis. After about 20 days of treatment, signs of parkinsonism occurred and the concentrations of NO and peroxidase products rose in the brain, especially in the striatum. After 60 days of treatment, rotenone had destroyed dopaminergic neurons. Behaviourally, catalepsy was evident, a hunchback posture and reduced locomotion. Other transmitter systems were not, or much less affected. L-DOPA-methylester (10 mg/kg plus decarboxylase inhibition) potently reversed the parkinsonism in rats. Also when infused directly into the dopaminergic neurons, rotenone produced parkinsonism which was antagonized by L-DOPA. Some peripheral symptoms of PD are mimiced by rotenone too, for example a low testosterone concentration in the serum and a loss of dopaminergic amacrine cells in the retina. These results support the hypothesis of an involvement of complex I in PD and render the rotenone model as a suitable experimental model. The slow onset of degeneration make it suitable also to study neuroprotective strategies. Evidence that rotenone-induced neurodegeneration spreads beyond the dopaminergic system is not contradictory given that, according to the new staging studies, also degeneration in PD is not confined to dopamine neurons.
Schmidt
W J
WJ
Department of Neuropharmacology, Zoological Institute, University of Tübingen, Germany. werner.schmidt@uni-tuebingen.de
Alam
M
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents; D006801:Humans; D009410:Nerve Degeneration / Q000473:pathology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000473:pathology*; D012402:Rotenone; D014475:Uncoupling Agents
D015259:Dopamine Agents; D014475:Uncoupling Agents; D012402:Rotenone; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine