Gene knockout approach to adenosine A2A receptors in Parkinson's disease
Gene knockout approach to adenosine A2A receptors in Parkinson's disease
复制标题
DOI：
10.1002/ddr.10215
复制
发表时间：
2003-04
影响因子：
3.8
通讯作者：
Jiang-fan Chen;M. Schwarzschild
中科院分区：
文献类型：
--
作者：
Jiang-fan Chen;M. Schwarzschild
最近，腺苷A2 A受体（A2 AR）由于其与纹状体中的多巴胺D2受体（D2 R）共表达及其对多巴胺受体介导的功能的调节而成为帕金森病（PD）治疗的有吸引力的靶点。此外，腺苷拮抗剂咖啡因最近在大型前瞻性流行病学研究中与降低发生PD的风险有关，这提高了咖啡因和更特异性的腺苷拮抗剂可能防止多巴胺能神经元死亡的可能性。最近，我们和其他人已经开发了一系列A2 AR和D2 R敲除（KO）小鼠模型。这些具有A2 AR和D2 R的完全、特异性遗传失活的突变小鼠模型克服了A2 A拮抗剂的一些内在局限性，并提供了研究A2 AR在PD发展和治疗中的作用的机会。首先，我们使用D2以及A2 AR KO小鼠通过确定A2 AR功能对D2受体的依赖性来剖析A2 AR作用的分子机制。A2 A拮抗剂（CSC）和非特异性拮抗剂咖啡因诱导的D2受体缺陷的幼稚和利血平小鼠的运动刺激。这些结果表明，A2 AR拮抗剂增强运动功能至少部分独立于D2受体。其次，我们探索了A2 AR在单侧6-羟基多巴胺损伤小鼠中L-多巴诱导的行为敏化发展中的作用，这是PD运动障碍的行为和神经化学特征的动物模型。A2 AR的基因失活显著减弱了左旋多巴诱导的旋转行为敏化的发展和持续性，并减弱了纹状体中强啡肽mRNA的诱导。结果表明，A2 AR在PD患者对长期左旋多巴治疗的持续适应不良运动障碍反应的发展中起着关键作用。最后，我们发现A2 AR的基因失活减弱了MPTP诱导的纹状体多巴胺和多巴胺转运蛋白（DAT）的耗竭以及黑质多巴胺能神经元的损失。总之，用遗传方法获得的这些结果表明，A2 AR失活可能对PD具有多种治疗益处：通过部分D2非依赖性机制增强运动，预防L-多巴诱导的行为敏化，以及减弱多巴胺能神经变性。组织特异性和诱导型A2 A KO小鼠模型的产生将进一步完善我们对A2 A受体在PD发展和治疗中作用的理解。Drug Dev. Res. 58：354-367，2003.© 2003 Wiley利斯公司
Recently, the adenosine A2A receptor (A2AR) has emerged as an attractive target for Parkinson's disease (PD) treatment by virtue of its coexpression with the dopamine D2 receptor (D2R) in the striatum and its modulation of dopamine receptor‐mediated functions. Moreover, the adenosine antagonist, caffeine, has recently been linked to a reduced risk of developing PD in large prospective epidemiological studies, raising the possibility that caffeine and more specific adenosine antagonists may protect against dopaminergic neuron death. Recently, we and others have developed a series of A2AR and D2R knockout (KO) mouse models. These mutant mouse models with complete, specific genetic inactivation of A2ARs and D2Rs overcome some of the intrinsic limitations of A2A antagonists and provide an opportunity to investigate A2AR's role in the development and treatment of PD. First, we used D2 as well as A2AR KO mice to dissect the molecular mechanism of the A2AR's action by determining the dependence of A2AR function on D2 receptors. The A2A antagonist (CSC) and the nonspecific antagonist caffeine induced motor stimulation in naive and reserpinized mice deficient in D2 receptor. These results suggest that A2AR antagonists enhance motor function at least partially independent of D2 receptors. Second, we explored the role of A2ARs in the development of L‐dopa‐induced behavioral sensitization in unilaterally 6‐hydroxydopamine‐lesioned mice, an animal model of the behavioral and neurochemical features of dyskinesia in PD. Genetic inactivation of A2ARs markedly attenuated the development and persistence of L‐dopa‐induced rotational behavioral sensitization and attenuated induction of dynorphin mRNA in the striatum. The results suggest that A2AR plays a critical role in the development of persistent maladaptive dyskinetic responses to chronic L‐dopa treatment in PD. Finally, we showed that genetic inactivation of A2ARs attenuates MPTP‐induced depletion of dopamine and dopamine transporter (DAT) in the striatum and loss of dopaminergic neurons in the substantia nigra. Together, these results obtained with genetic approaches demonstrate that A2AR inactivation may have multiple therapeutic benefits for PD: motor enhancement through a partial D2‐independent mechanism, prevention of L‐dopa‐induced behavioral sensitization, and attenuation of dopaminergic neurodegeneration. The generation of tissue‐specific and inducible A2A KO mouse models will further refine our understanding of the A2A receptor's role in the development and treatment of PD. Drug Dev. Res. 58:354–367, 2003. © 2003 Wiley‐Liss, Inc.