Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions

Annals of Neurology - Tập 43 Số 5 - Trang 561-575 - 1998
M. Gustavo Murer1, Gustavo Dziewczapolski2, Liliana Menalled2, M. C. Garcı́a2, Yves Agid3, Oscar S. Gershanik2, Rita Raisman‐Vozari3
1INSERM U289, Hôpital de la Salpêtrière, Paris, France
2Instituto de Investigaciones Farmacológicas-CONICET, Buenos Aires, Argentina
3INSERM U289 Hǒpital de la Salpětrière Paris, France

Tóm tắt

AbstractOrally administered levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD). The introduction of levodopa therapy is often delayed, however, because of the fear that it might be toxic for the remaining dopaminergic neurons and, thus, accelerate the deterioration of patients. However, in vivo evidence of levodopa toxicity is scarce. We have evaluated the effects of a 6‐month oral levodoapa treatment on several dopaminergic markers, in rats with moderate or severe 6‐hydroxydopamine‐induced lesions of mesencephalic dopamine neurons and sham‐lesioned animals. Counts of tyrosine hydroxylase (TH)‐immunoreactive neurons in the substantia nigra and ventral tegmental area showed no significant difference between levodopa‐treated and vehicle‐treated rats. In addition, for rats of the sham‐lesioned and severely lesioned groups, immunoradiolabeling for TH, the dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) at the striatal level was not significantly defferent between rats treated with levodopa or vehicle. It was unexpected that quantification of immunoautoradiograms showed a partial recovery of all three dopaminergic markers (TH, DAT, and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa. Furthermore, the density of TH‐positive fibers observed in moderately lesioned rats was higher in those treated chronically with levodopa than in those receiving vehicle. Last, that chronic levodopa administration reversed the up‐regulation of D2 dopamine receptors seen in severely lesioned rats provided evidence that levodopa reached a biologically active concentration at the basal ganglia. Our results demonstrate that a pharmacologically effective 6‐month oral levodopa treatment is not toxic for remaining dopamine neurons in a rat model of PD but instead promotes the recovery of striatal innervation in rats with partial lesions.

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Annals of Neurology

Tập 43 Số 5

561-575

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