Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors increase their efficacy in reversing parkinsonian deficits in rats
Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors increase their efficacy in reversing parkinsonian deficits in rats
复制标题
DOI：
10.1038/sj.npp.1300444
复制
发表时间：
2004-08-01
影响因子：
7.6
通讯作者：
Amalric, M
中科院分区：
文献类型：
--
作者：
Coccurello, R;Breysse, N;Amalric, M
最近的证据表明，腺苷A（2A）受体的拮抗剂代表了帕金森病（PD）的替代治疗方法。A（2A）和谷氨酸亚型5代谢型受体（mGlu（5））的共激活协同刺激纹状体中DARPP-32磷酸化和c-fos表达。因此，本研究测试了联合阻断这些受体对减轻PD大鼠模型中运动功能障碍的作用。6-纹状体中的羟基多巴胺输注产生运动障碍的大鼠训练释放杠杆刺激后的反应时间（RT）任务。在损伤后2周，A（2A）和mGlu（5）受体选择性拮抗剂8-（3-氯苯乙烯基）咖啡因（CSC）和2-甲基-6-（苯乙炔基）-吡啶（MPEP）作为单一或联合治疗每天施用3周。CSC（1.25 mg/kg）和MPEP（1.5 mg/kg）单独或联合注射可减少6-OHDA损伤诱导的延迟反应和RT的增加，而相同的治疗对对照组无影响。此外，低剂量的0.625 mg/kg CSC和0.375 mg/kg MPEP联合给药无效，单次给药可促进运动不能的完全和立即恢复，发现这比单独阻断这些受体更有效。这些结果表明，A（2A）和mGlu（5）受体的联合失活增强了其有益作用，支持这种药理学策略作为一种有前途的抗帕金森病治疗。
Recent evidence suggest that antagonism of adenosine A(2A) receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A(2A) and the glutamate subtype 5 metabotropic receptors (mGlu(5)) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum, This study therefore tested the effects of a joint blockade of these receptor's to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A(2A) and mGlu(5) receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A(2A) and mGlu(5) receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.