Panorama Research Institute, Sunnyvale, California, USA.
Regenerative Sciences Institute, Sunnyvale, California, USA.
Rejuvenation Res. 2021 Feb;24(1):65-67. doi: 10.1089/rej.2021.0004.
Inflammaging is associated with aging-associated cognitive loss and neurodegeneration. Chronic nonsteroidal anti-inflammatory drug (NSAID) use has been reported to reduce the incidence of Alzheimer's disease (AD), presumably by inhibiting inflammation, although NSAIDs appear to not be good candidates for anti-AD therapeutics given disappointing clinical trial results. Prostaglandin E2 (PGE2) acts downstream of NSAID target COX-2, a cyclooxygenase, to activate several G-protein coupled receptors (GPCRs) including EP2, which is now reported to reduce glycolysis and oxidative phosphorylation during aging by increasing glycogen synthesis and polarizing myeloid cells toward the M1 proinflammatory phenotype. Inhibiting EP2 using small molecule drugs polarizes macrophages toward the anti-inflammatory phenotype, restores youthful metabolism and mitochondrial morphology as well as youthful hippocampus-based memory capability. EP2 may be a better target than COXs for the development of drugs that improve age-associated mild cognitive impairment and possibly even for the development of drugs to treat dementias.
炎症与衰老相关的认知能力下降和神经退行性变有关。据报道，慢性非甾体抗炎药（NSAID）的使用可以降低阿尔茨海默病（AD）的发病率，推测是通过抑制炎症，尽管 NSAID 似乎不是治疗 AD 的好候选药物，因为临床试验结果令人失望。前列腺素 E2（PGE2）作为 NSAID 靶标 COX-2 的下游产物，激活几种 G 蛋白偶联受体（GPCR），包括 EP2，据报道，EP2 通过增加糖原合成并将髓样细胞极化到 M1 促炎表型，在衰老过程中减少糖酵解和氧化磷酸化。使用小分子药物抑制 EP2 可使巨噬细胞向抗炎表型极化，恢复年轻的代谢和线粒体形态，以及年轻的海马记忆能力。EP2 可能是比 COXs 更好的药物靶点，用于改善与年龄相关的轻度认知障碍，甚至可能用于开发治疗痴呆症的药物。
