Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612.
Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612.
Proc Natl Acad Sci U S A. 2018 Jul 31;115(31):E7408-E7417. doi: 10.1073/pnas.1802021115. Epub 2018 Jul 16.
Despite its long history, until now, no receptor has been identified for aspirin, one of the most widely used medicines worldwide. Here we report that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor involved in fatty acid metabolism, serves as a receptor of aspirin. Detailed proteomic analyses including cheminformatics, thermal shift assays, and TR-FRET revealed that aspirin, but not other structural homologs, acts as a PPARα ligand through direct binding at the Tyr314 residue of the PPARα ligand-binding domain. On binding to PPARα, aspirin stimulated hippocampal plasticity via transcriptional activation of cAMP response element-binding protein (CREB). Finally, hippocampus-dependent behavioral analyses, calcium influx assays in hippocampal slices and quantification of dendritic spines demonstrated that low-dose aspirin treatment improved hippocampal plasticity and memory in FAD5X mice, but not in FAD5X/-null mice. These findings highlight a property of aspirin: stimulating hippocampal plasticity via direct interaction with PPARα.
尽管阿司匹林已有很长的历史，但直到现在，还没有发现它的受体。阿司匹林是世界上使用最广泛的药物之一。在这里，我们报告过氧化物酶体增殖物激活受体α（PPARα），一种参与脂肪酸代谢的核激素受体，是阿司匹林的受体。详细的蛋白质组学分析包括化学信息学、热移位测定和 TR-FRET 揭示，阿司匹林而不是其他结构类似物，通过直接结合 PPARα 配体结合域的 Tyr314 残基，作为 PPARα 的配体。与 PPARα 结合后，阿司匹林通过激活 cAMP 反应元件结合蛋白（CREB）的转录激活来刺激海马体的可塑性。最后，海马依赖性行为分析、海马切片中的钙内流测定和树突棘的定量分析表明，低剂量阿司匹林治疗可改善 FAD5X 小鼠的海马体可塑性和记忆，但不能改善 FAD5X/-null 小鼠的海马体可塑性和记忆。这些发现强调了阿司匹林的一个特性：通过与 PPARα 的直接相互作用刺激海马体的可塑性。
