Carta Anna R, Tabrizi Mojgan Aghazadeh, Baraldi Pier G, Pinna Annalisa, Pala Paola, Morelli Micaela
Department of Toxicology and Centre of Excellence for Neurobiology of Dependence, University of Cagliari, 09124 Cagliari, Italy.
Exp Neurol. 2003 Dec;184(2):679-87. doi: 10.1016/S0014-4886(03)00292-9.
Studies in animal models of Parkinson's disease (PD) suggest the potential utility of adenosine A(2A) antagonists in the treatment of this disease. In the present study, unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats received chronic intermittent treatment with the adenosine A(2A) antagonist SCH58261 (5 mg/kg) plus l-DOPA (3 mg/kg) or l-DOPA (6 mg/kg) alone, at doses producing the same intensity of contralateral turning on first administration. Three days after discontinuation of treatments, GABA synthesizing enzyme glutamic acid decarboxylase (GAD67) mRNA was evaluated at cellular level in the globus pallidus (GP) and substantia nigra pars reticulata (SNr) by in situ hybridization. 6-OHDA lesion significantly increased GAD67 mRNA levels in both the GP and SNr ipsilateral to the lesion. Chronic l-DOPA (6 mg/kg), in contrast to SCH58261 plus l-DOPA (3 mg/kg), produced a sensitized contralateral turning indicative of dyskinetic potential and further increased GAD67 mRNA in the GP. In the SNr, a significant decrease in GAD67 mRNA was observed after either treatments. However, while l-DOPA (6 mg/kg) decreased SNr GAD67 mRNA below the intact side, SCH58261 plus l-DOPA (3 mg/kg) brought GAD67 mRNA to the same level of the intact SNr. l-DOPA (3 mg/kg) or SCH58261 (5 mg/kg) alone failed to modify GAD67 mRNA. Results suggest that an increase in GAD67 mRNA in GP and a decrease in SNr might underlie dyskinetic movements induced by chronic l-DOPA. In contrast, the lack of GAD67 mRNA changes in the GP and a less marked inhibition of SNr might correlate with the absence of dyskinetic potential observed after SCH58261 plus l-DOPA.
帕金森病（PD）动物模型研究表明，腺苷A(2A)拮抗剂在治疗该疾病方面具有潜在效用。在本研究中，单侧6-羟基多巴胺（6-OHDA）损伤的大鼠接受了腺苷A(2A)拮抗剂SCH58261（5毫克/千克）加左旋多巴（3毫克/千克）或单独使用左旋多巴（6毫克/千克）的慢性间歇性治疗，给药剂量在首次给药时产生相同强度的对侧旋转。停药三天后，通过原位杂交在细胞水平评估苍白球（GP）和黑质网状部（SNr）中γ-氨基丁酸合成酶谷氨酸脱羧酶（GAD67）mRNA的表达。6-OHDA损伤显著增加了损伤同侧GP和SNr中的GAD67 mRNA水平。与SCH58261加左旋多巴（3毫克/千克）相比，慢性左旋多巴（6毫克/千克）产生了表明有异动症潜能的敏感对侧旋转，并进一步增加了GP中的GAD67 mRNA。在SNr中，两种治疗后均观察到GAD67 mRNA显著下降。然而，虽然左旋多巴（6毫克/千克）使SNr GAD67 mRNA低于完整侧，但SCH58261加左旋多巴（3毫克/千克）使GAD67 mRNA达到完整SNr的相同水平。单独使用左旋多巴（3毫克/千克）或SCH58261（5毫克/千克）未能改变GAD67 mRNA。结果表明，GP中GAD67 mRNA增加和SNr中减少可能是慢性左旋多巴诱导异动症的基础。相比之下，GP中GAD67 mRNA缺乏变化以及对SNr的抑制作用不明显可能与SCH58261加左旋多巴后未观察到异动症潜能有关。
