特別演講2:

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P-6
A2A腺甘酸受體藥物的發展及在神經退化性疾病上的應用
A2A adenosine receptor and neurodegenerative diseases
陳儀莊
中央研究院生物醫學研究所
(故杜聰明博士紀念演講獎)

  The A2A adenosine receptor (A2AR) is a major target of caffeine, the most widely used psychoactive substance in the world. It contains seven transmembrane domains and belongs to the G protein-coupled receptor (GPCR) family. In the brain, the A2AR gene is heavily expressed in GABAergic striopallidal neurons, which selectively degenerate during the progression of Huntington’s disease (HD). Many other brain areas (such as the cortex and spinal cord) also contain A2AR at low levels. We previously showed that stimulation of A2AR activates multiple signaling pathways (including the cAMP/protein kinase A (PKA)) and exerts a protective effect on neuronal cell lines against stresses. Using a transgenic mouse model (R6/2) of HD, we further demonstrated that activation of A2AR effectively ameliorates several major symptoms of HD through at least three cAMP-dependent protective mechanisms: (i) enhancing the expression of pro-survival genes (e.g., Bcl2), (ii) reducing aggregates of mHTT in vitro and in vivo by enhancing the activity of the proteasome system, and (iii) suppressing the abnormal activation and translocalization of an energy sensor (AMPK-α1) into the nuclei of striatal cells. Together with the findings from other laboratories, the potential role of A2AR in neurodegenerative diseases has attracted much attention in the past decade. However, because A2AR is also located in many peripheral tissues, most of the currently available A2AR agonists have unpleasant side effects (mostly in the cardiac vascular system) that prevent their clinical applications. To develop novel A2AR drugs for neurodegenerative diseases that, we collaborated with a team of excellent scientists led by Drs. Yun-Lian Lin and Jim-Min Fang to screen for adenosine analogues from Chinese herbs, and further designed and synthesized novel adenosine compounds that stimulate A2AR. These adenosine compounds have moderate affinities toward A2AR and thus do not cause significant peripheral side effects. Importantly, they are capable of pass through the blood-brain-barrier to enter the brain, and to exert neuroprotective effects in diseased mice by activating A2AR and enhancing the adenosine tone in the brain. Chronic treatment with these adenosine drugs resulted in beneficial effects in mouse models of several degenerative diseases that are associated with abnormal accumulation of protein aggregates in the brain. Collectively, A2AR is worthy of further investigation as a drug target for neurodegenerative diseases.