Ferrario Juan Esteban, Rojas-Mayorquín Argelia Esperanza, Saldaña-Ortega Marisa, Salum Cristiane, Gomes Margarete Zanardo, Hunot Stéphane, Raisman-Vozari Rita
INSERM, UMR 5679, F-75013, Paris, France.
J Neurochem. 2008 Oct;107(2):443-52. doi: 10.1111/j.1471-4159.2008.05640.x. Epub 2008 Sep 16.
L-DOPA is still the drug of choice to treat Parkinson's disease although adverse side effects appear after several years of treatment. These are thought to be the consequence of plastic re-arrangements of the nigrostriatal connections, such as sprouting of the dopaminergic terminals or post-synaptic changes. Pleiotrophin, a trophic factor that we have shown to be up-regulated in the striatum of parkinsonian rats after long-term L-DOPA treatment may play a role in these plastic changes. To determine whether one of the three known pleiotrophin receptors [N-syndecan, receptor protein tyrosine phosphatase type zeta beta (RPTP-zeta/beta) and anaplastic lymphoma kinase] might be implicated in these putative plastic effects, we quantified their expression levels by real-time RT-PCR in the striatum and mesencephalon of rats with partial lesions of the nigrostriatal pathway undergoing L-DOPA treatment. Both pleiotrophin and RPTP-zeta/beta expression was up-regulated in the striatum but not in the mesencephalon of lesioned rats and RPTP-zeta/beta expression was even further increased by L-DOPA. The levels of the RPTP-zeta/beta protein were also increased in the striatum of L-DOPA-treated lesioned rats. Immunofluorescence labeling showed the protein to be constitutively expressed in striatal medium spiny neurons, which are innervated by both the corticostriatal glutamatergic and nigrostriatal dopaminergic systems. RPTP-zeta/beta might therefore be implicated in the plastic changes triggered by L-DOPA treatment and might merit further study as a potential candidate for Parkinon's disease therapy.
左旋多巴仍然是治疗帕金森病的首选药物，尽管在治疗数年之后会出现不良副作用。这些副作用被认为是黑质纹状体连接发生可塑性重排的结果，比如多巴胺能终末的发芽或突触后变化。多效生长因子是一种营养因子，我们已经证明在长期左旋多巴治疗后的帕金森病大鼠纹状体中其表达上调，它可能在这些可塑性变化中发挥作用。为了确定三种已知的多效生长因子受体（N-聚糖蛋白聚糖、zeta beta型受体蛋白酪氨酸磷酸酶和间变性淋巴瘤激酶）中的一种是否与这些假定的可塑性效应有关，我们通过实时逆转录聚合酶链反应（RT-PCR）对接受左旋多巴治疗的黑质纹状体通路部分损伤大鼠的纹状体和中脑内它们的表达水平进行了定量分析。在损伤大鼠的纹状体中，多效生长因子和zeta beta型受体蛋白酪氨酸磷酸酶（RPTP-zeta/beta）的表达均上调，但在中脑中未上调，并且左旋多巴使RPTP-zeta/beta的表达进一步增加。在接受左旋多巴治疗的损伤大鼠的纹状体中，RPTP-zeta/beta蛋白的水平也升高。免疫荧光标记显示该蛋白在纹状体中等棘状神经元中组成性表达，这些神经元接受皮质纹状体谷氨酸能和黑质纹状体多巴胺能系统的支配。因此，RPTP-zeta/beta可能与左旋多巴治疗引发的可塑性变化有关，并且作为帕金森病治疗的潜在候选物可能值得进一步研究。
