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腺苷A2A受体拮抗剂对左旋多巴诱发异动症大鼠行为、纹状体A2A受体和代谢型谷氨酸受体5亚型蛋白表达的影响 被引量:3

The effects of adenosine A2A receptor antagonist on the behavior and the striatal A2A receptor,metabotropic glutamate receptors protein expression in rats with levodopa-induced dyskinesia
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摘要 目的 评价腺苷A2A受体拮抗剂(CSC)对左旋多巴(L-DOPA)诱发异动症大鼠行为、纹状体A2A受体和代谢型谷氨酸受体5亚型(mGluR5)蛋白表达的影响.方法 6-羟多巴胺(6-OHDA)立体定向损毁大鼠右内侧前脑束,建立单侧损毁帕金森病(PD)大鼠模型.采用随机数字表法将40只成功PD大鼠随机分为4组(每组10只):生理盐水组;L-DOPA 25 mg/kg+苄丝肼6.25 mg/kg组;CSC 2.5 mg/kg组;L-DOPA 25 mg/kg+苄丝肼6.25 mg/kg联合CSC 2.5 mg/kg组.给予大鼠每日2次腹腔注射,持续21 d.在治疗第2、9、11、18、21天观察大鼠行为学变化,Western blot检测纹状体区腺苷A2A受体和mGluR5的蛋白表达水平.结果 L-DOPA联合CSC组PD大鼠损毁对侧前肢跨步数显著增加,与治疗前比较差异有统计学意义,与L-DOPA组相比,前肢功能改善程度不随时间延长而减弱.单独CSC组治疗后对侧前肢跨步数明显增加,与治疗前比较差异有统计学意义,有疗效逐渐增加至稳定趋势.L-DOPA联合CSC组[(11±5)分]部分口颌及肢体异常不自主运动评分较L-DOPA组[(17±4)分]显著减少,差异有统计学意义(t=2.44,P<0.05).L-DOPA联合CSC治疗逆转了L-DOPA诱导的对侧旋转反应时间缩短和腺苷A2A受体、mGluR5蛋白表达的上调,差异均有统计学意义.结论 腺苷A2A受体与mGluR5均参与了L-DOPA诱发的异动症的发生发展,A2A受体拮抗剂能够改善PD运动症状,增强L-DOPA的抗PD效应且部分减轻异常不自主运动,对L-DOPA诱发的异动症的治疗有着较好的应用前景. Objective To study the behavioural changes and biological effects of selective adenosine A2A receptor antagonist (CSC) in a rat model of levodopa(L-DOPA) -induced dyskinesia (LID).Methods The hemi-parkinsonian rat model was produced by stereotaxically injecting 6-OHDA to the right medial forebrain bundle. Rats were randomly divided into 4 treatment groups with a random number generating program to receive intraperitoneal injections twice daily for 21 days (n = 10): saline, L-DOPA at 25 mg/kg with benserazide at 6. 25 mg/kg, CSC at 2. 5 mg/kg alone and CSC at 2.5 mg/kg with L-DOPA at 25 mg/kg plus benserazide at 6. 25 mg/kg. Forepaw adjusting steps, abnormal involuntary movements (AIM) and rotational response duration were observed on 2, 9, 11,18 and 21 d. After sacrifice, the expression of adenosine A2A R and mGluR5 was observed by Western blot. Results Co-administration of LDOPA with CSC significantly increased the forelimb adjusting steps of parkinsonian rats during 21 days of treatment when compared to L-DOPA alone. CSC treatment alone increased the forelimb adjusting steps significantly. Co-administration of L-DOPA with CSC ( ( 11 ± 5 ) score) significantly decreased the AIM scores of limb and orolingual muscles when compared to L-DOPA alone (( 17 ± 4) score; t = 2. 44, P 〈0. 05). The subchronic L-DOPA treatment upregulated the striatal expression of adenosine A2A R and mGluR5. However, co-administration of L-DOPA with CSC reversed the shortening of the rotational motor response duration induced by L-DOPA administration during the period of the treatment and attenuated the LDOPA-induced upregulation of adenosine A2A R and mGluR5 expressions. Conclusions CSC improves motor function in a hemi-parkinson rat model, potentiates the antiparkinsonian effects with L-DOPA and partly attenuates LID. Co-administration of L-DOPA with CSC reverses the L-DOPA-induced upregulated expression of A2A R and mGluR5, indicating the involvement of both A2A R and mGluR5 in the onset and progression of LID. Adenosine A2AR antagonists may be promising drugs for treatment of LID.
出处 《中华神经科杂志》 CAS CSCD 北大核心 2011年第2期122-127,共6页 Chinese Journal of Neurology
基金 江苏省"六大人才高峰"资助项目(07-B-005) 苏州大学科技创新培育工程重大项目(SZ123819)
关键词 运动障碍 药物性 咖啡因 受体 腺苷A2A 受体 亲代谢性谷氨酸盐 左旋多巴 大鼠 Dyskinesia, drug-induced Caffeine Receptor, adenosine A2A Receptor,metabotropic glutamate Levodopa Rats
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参考文献14

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共引文献43

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