Jenner P, Mori A, Hauser R, Morelli M, Fredholm B B, Chen J F
Neurodegenerative Diseases Research Centre, School of Health and Biomedical Sciences, King's College, London SE1 1UL, UK.
Parkinsonism Relat Disord. 2009 Jul;15(6):406-13. doi: 10.1016/j.parkreldis.2008.12.006. Epub 2009 May 15.
Adenosine derived from the degradation of ATP/AMP functions as a signalling molecule in the nervous system through the occupation of A1, A2, and A3 adenosine receptors. Adenosine A(2A) receptors have a selective localization to the basal ganglia and specifically to the indirect output pathway, and as a consequence offer a unique opportunity to modulate the output from the striatum that is believed critical to the occurrence of motor components of PD. Indeed, the ability of A(2A) antagonists to modulate basal ganglia neurotransmission has been shown to be associated with improved motor function in experimental models of PD. This suggests that A(2A) antagonists would be effective as a symptomatic treatment in humans without provoking marked dyskinesia. Indeed, the A(2A) antagonist istradefylline reduces OFF time in moderate- to late-stage patients with PD already receiving dopaminergic therapy, with an increase in non-troublesome dyskinesia. Adenosine and adenosine receptors also exert actions relevant to pathogenesis in PD, raising the possibility of their use as neuroprotective agents. Both epidemiologic evidence and the current preclinical data strongly support a role for A(2A) antagonists in protecting dopaminergic neurons and influencing the onset and progression of PD.
由ATP/AMP降解产生的腺苷在神经系统中作为信号分子，通过占据A1、A2和A3腺苷受体发挥作用。腺苷A(2A)受体选择性定位于基底神经节，特别是间接输出通路，因此提供了一个独特的机会来调节纹状体的输出，而纹状体输出被认为对帕金森病运动成分的发生至关重要。事实上，在帕金森病实验模型中，A(2A)拮抗剂调节基底神经节神经传递的能力已被证明与运动功能改善有关。这表明A(2A)拮抗剂作为一种对症治疗药物，在人类中有效且不会引发明显的运动障碍。的确，A(2A)拮抗剂异他林减少了已经接受多巴胺能治疗的中晚期帕金森病患者的“关”期时间，同时增加了不麻烦的运动障碍。腺苷和腺苷受体在帕金森病发病机制中也发挥相关作用，这增加了它们用作神经保护剂的可能性。流行病学证据和当前临床前数据都有力地支持A(2A)拮抗剂在保护多巴胺能神经元以及影响帕金森病的发病和进展方面的作用。
