Murer M G, Dziewczapolski G, Menalled L B, García M C, Agid Y, Gershanik O, Raisman-Vozari R
INSERM U289, Hôpital de la Salpêtrière, Paris, France.
Ann Neurol. 1998 May;43(5):561-75. doi: 10.1002/ana.410430504.
Orally 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 levodopa 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 different 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.
口服左旋多巴仍然是帕金森病（PD）最有效的对症治疗方法。然而，左旋多巴疗法的引入往往会延迟，因为担心它可能对剩余的多巴胺能神经元有毒性，从而加速患者病情的恶化。然而，左旋多巴毒性的体内证据很少。我们评估了为期6个月的口服左旋多巴治疗对中度或重度6-羟基多巴胺诱导的中脑多巴胺神经元损伤大鼠和假手术动物的几种多巴胺能标志物的影响。黑质和腹侧被盖区酪氨酸羟化酶（TH）免疫反应性神经元的计数显示，左旋多巴治疗组和载体治疗组大鼠之间没有显著差异。此外，对于假手术组和重度损伤组的大鼠，左旋多巴或载体治疗的大鼠在纹状体水平上TH、多巴胺转运体（DAT）和囊泡单胺转运体（VMAT2）的免疫放射标记没有显著差异。出乎意料的是，免疫放射自显影片的定量分析显示，接受左旋多巴治疗的中度损伤大鼠纹状体去神经支配区域的所有三种多巴胺能标志物（TH、DAT和VMAT2）都有部分恢复。此外，在中度损伤大鼠中观察到的TH阳性纤维密度，长期接受左旋多巴治疗的大鼠高于接受载体治疗的大鼠。最后，长期给予左旋多巴可逆转重度损伤大鼠中D2多巴胺受体的上调，这证明左旋多巴在基底神经节达到了生物活性浓度。我们的结果表明，为期6个月的口服左旋多巴药物有效治疗对PD大鼠模型中剩余的多巴胺神经元没有毒性，反而促进了部分损伤大鼠纹状体神经支配的恢复。
