Fachbereich Veterinärmedizin



    Mouse models of parkinsonism: effects of chronic treatment with rotenone and subchronic intrastriatal 6-OHDA injections (2006)

    Richter, F.
    Hamann, M.
    Richter, A.
    Annual meeting of the Society for Neuroscience
    Atlanta, Georgia/USA, 14. – 18.10.2006
    2006 Neuroscience Meeting Planner
    — S. Program No. 275.7.
    Institut für Pharmakologie und Toxikologie

    Koserstr. 20
    14195 Berlin
    +49 30 838 53221

    Abstract / Zusammenfassung

    In Parkinson´s disease (PD) the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) is probably caused by environmental factors (e.g., exposure to pesticides, such as rotenone) combined with aging and genetic predisposition. Chronic systemic treatment with rotenone and acute intrastriatal injections of neurotoxic 6-OHDA have been reported to induce parkinsonism in rats. In order to identify neuroprotective agents, there is a need for PD models with progressive neurodegeneration. We examined the effects of comparable treatments in intact mice to provide a basis for studying the impact of toxin exposure in genetic mouse models of PD.
    Therefore, we investigated the effects of chronic exposure to rotenone (2.5 or 4.0 mg/kg s.c. for 45 d) in C57Bl/6 mice at an age of 2.5, 5 or 12 months. In addition, we examined if repeated intrastriatal applications of low doses of 6-OHDA (8 µg) for 5 or 7 d vs. single microinjections provoke a progressive retrograde degeneration of SNc neurons in C57Bl/6 mice. During the treatment period the effects on vitality and motor behaviour were investigated. Furthermore, the toxic effects on dopaminergic nigrostriatal neurons and peripheral tissues were examined.
    In comparison with control animals, rotenone-treated mice had a decreased spontaneous motor activity, but the density of nigral dopaminergic neurons failed to show any significant changes, except for a tendency to reduction in old mice treated with 4 mg/kg. In contrast to an acute intrastriatal injection of 6-OHDA, administration over 5 d provoked a visible decrease of nigrostriatal terminals and a moderate loss of SNc neurons in the absence of behavioural effects. Treatment over 7 d revealed no further aggravation of degeneration, but a slight cataleptic behaviour.
    The data indicate that rotenone is not able to cause the neuropathological characteristics of PD in intact mice under the testing paradigms which have been reported to cause parkinsonism in rats. Subchronic intrastriatal injections of 6-OHDA in mice produced a moderate degeneration of dopaminergic neurons accompanied by moderate catalepsy, as described for early stages of PD. Further studies have to clarify if genetic mouse models of PD might be more sensitive to the neurotoxic effects.