Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy.
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy.
Molecules. 2022 Apr 21;27(9):2680. doi: 10.3390/molecules27092680.
The A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer's disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-β extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A adenosine receptors in AD animal and human studies and reports the state of the art of A adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood-brain barrier in the discovery of new agents for treating CNS disorders. Considering that A receptor antagonist istradefylline is already commercially available for Parkinson's disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients.
A 腺苷受体是一种属于四个 GPCR 腺苷受体家族的蛋白。它参与了中枢神经系统和外周组织中几种病理生理状况的调节。在大脑中，它在纹状体、皮层、海马体的突触前和突触后水平的定位及其对谷氨酸释放、小胶质细胞和星形胶质细胞激活的影响，使其在神经退行性疾病中发挥着关键作用，包括阿尔茨海默病（AD）。这种疾病被认为是痴呆的主要形式，预计在未来几年会呈指数级增长。AD 的病理途径包括淀粉样肽-β 细胞外积累和 tau 过度磷酸化，导致神经元细胞死亡、认知缺陷和记忆丧失。有趣的是，体外和体内研究表明，A 腺苷受体拮抗剂可能对抗这些临床症状，这代表了对抗这种疾病的一个重要新策略，不幸的是，目前只有对症药物可用。本综述简要概述了 A 腺苷受体在 AD 动物和人类研究中的生物学作用，并报告了目前处于临床试验阶段的 A 腺苷受体拮抗剂的最新进展。作为一种创新方法，它侧重于药代动力学和穿过血脑屏障的能力在发现治疗中枢神经系统疾病的新药物方面的关键作用。考虑到 A 受体拮抗剂伊曲茶碱已可用于治疗帕金森病，如果这些配体在 AD 中的概念验证得到证实和加强，那么为 AD 患者提供新的希望将变得更加容易。
