Deletion of adenosine A₁ or A(₂A) receptors reduces L-3,4-dihydroxyphenylalanine-induced dyskinesia in a model of Parkinson's disease.
Deletion of adenosine A₁ or A(₂A) receptors reduces L-3,4-dihydroxyphenylalanine-induced dyskinesia in a model of Parkinson's disease.
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DOI：
10.1016/j.brainres.2010.08.099
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发表时间：
2011-01-07
期刊：
影响因子：
2.9
通讯作者：
Schwarzschild MA
中科院分区：
文献类型：
--
作者：
Xiao D;Cassin JJ;Healy B;Burdett TC;Chen JF;Fredholm BB;Schwarzschild MA
腺苷A2 A受体拮抗剂为开发帕金森病（PD）的非多巴胺能治疗提供了一种有前途的方法。A2 A拮抗剂的临床试验已经靶向具有L-3，4-二羟基苯丙氨酸（L-DOPA）诱导的运动障碍（LID）的PD患者，以努力改善帕金森病症状。腺苷在LID发展中的作用知之甚少，特别是关于其通过A1受体的作用。我们的目的是研究的影响，遗传缺失和药理学阻断A1和/或A2 A受体的发展LID，诱导LID的分子标记物，包括纹状体前强啡肽原和前脑啡肽原（PPE），和多巴胺能黑质纹状体神经元的完整性在偏侧帕金森病小鼠。在单侧6-羟基多巴胺损伤A1、A2 A和双A1-A2 A敲除（KO）和野生型同窝小鼠以及用咖啡因（A1和A2 A受体的拮抗剂）或盐水预处理的小鼠之后，每天用低剂量的L-DOPA处理18-21天。在A1和A2 A科斯中，总的异常不自主运动（AIM，LID的测量）显著减弱（p<0.05），但在A1-A2 A科斯和咖啡因预处理的小鼠中没有。WT小鼠病变同侧PPE mRNA的升高在所有KO小鼠中均降低。此外，通过纹状体多巴胺含量评估的神经元完整性在6-羟基多巴胺损伤后的所有科斯和咖啡因预处理的小鼠中相似。我们的研究结果提出了A1或A2 A受体阻断也可能赋予疾病改善的好处，降低致残LID的风险，而它们的联合失活的效果不太清楚。
Adenosine A2A receptor antagonism provides a promising approach to developing nondopaminergic therapy for Parkinson’s disease (PD). Clinical trials of A2A antagonists have targeted PD patients with L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve parkinsonian symptoms. The role of adenosine in the development of LID is little known, especially regarding its actions via A1 receptors. We aimed to examine the effects of genetic deletion and pharmacological blockade of A1 and/or A2A receptors on the development of LID, on the induction of molecular markers of LID including striatal preprodynorphin and preproenkephalin (PPE), and on the integrity of dopaminergic nigrostriatal neurons in hemiparkinsonian mice. Following a unilateral 6-hydroxydopamine lesion A1, A2A and double A1-A2A knockout (KO) and wild-type littermate mice, and mice pretreated with caffeine (an antagonist of both A1 and A2A receptors) or saline were treated daily for 18–21 days with a low dose of L-DOPA. Total abnormal involuntary movements (AIMs, a measure of LID) were significantly attenuated (p<0.05) in A1 and A2A KOs, but not in A1-A2A KOs and caffeine-pretreated mice. An elevation of PPE mRNA ipsilateral to the lesion in WT mice was reduced in all KO mice. In addition, neuronal integrity assessed by striatal dopamine content was similar in all KOs and caffeine-pretreated mice following 6-hydroxydopamine lesioning. Our findings raise the possibility that A1 or A2A receptors blockade might also confer a disease-modifying benefit of reduced risk of disabling LID, whereas the effect of their combined inactivation is less clear.
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