Oxenkrug Gregory
Department of Psychiatry, Tufts University School of Medicine, Boston, MA 02111, USA.
Int J Mol Sci. 2024 Dec 10;25(24):13269. doi: 10.3390/ijms252413269.
Cognitive impairment is a core feature of neurodevelopmental (schizophrenia) and aging-associated (mild cognitive impairment and Alzheimer's dementia) neurodegenerative diseases. Limited efficacy of current pharmacological treatments warrants further search for new targets for nootropic interventions. The breakdown of myelin, a phospholipids axonal sheath that protects the conduction of nerve impulse between neurons, was proposed as a neuropathological abnormality that precedes and promotes the deposition of amyloid-β in neuritic plaques. The present review of the recent literature and our own pre- and clinical data suggest (for the first time) that the anthranilic acid (AA)-induced activation of microglial-expressed G-protein coupled receptor (GPR109A) inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that triggers the degradation of myelin and consequently attenuates cognitive impairment. The present review suggests that the up-regulation of AA formation is a sex-specific compensatory (adaptive) reaction aimed to prevent/treat cognitive impairment. The AA-GPR109A-cPLA2-myelin-cognition cascade suggests new nootropic interventions, e.g., the administration of pegylated kynureninase, an enzyme that catalyzes AA formation from Kynurenine (Kyn), a tryptophane catabolite; pegylated interferon-alpha; central and peripheral Kyn aminotransferase inhibitors that increase availability of Kyn as a substrate for AA formation; and vagus nerve stimulation. The cascade predicts nootropic activity of exogenous GPR109A agonists that were designed and underwent clinical trials (unsuccessful) as anti-dyslipidemia agents. The proposed cascade might contribute to the pathogenesis of cognitive impairment. Data on AA in neurodegenerative disorders are scarce, and the proposed cascade needs further exploration in pre- and clinical studies.
认知障碍是神经发育性（精神分裂症）和与衰老相关的（轻度认知障碍和阿尔茨海默病性痴呆）神经退行性疾病的核心特征。当前药物治疗效果有限，这使得有必要进一步寻找促智干预的新靶点。髓鞘是一种保护神经元之间神经冲动传导的磷脂轴突鞘，其破坏被认为是一种神经病理学异常，它先于并促进淀粉样β蛋白在神经炎性斑块中的沉积。对近期文献以及我们自己的临床前和临床数据的综述首次表明，邻氨基苯甲酸（AA）诱导的小胶质细胞表达的G蛋白偶联受体（GPR109A）激活会抑制胞质磷脂酶A2（cPLA2），该酶会引发髓鞘降解，从而减轻认知障碍。本综述表明，AA生成的上调是一种性别特异性的代偿性（适应性）反应，旨在预防/治疗认知障碍。AA - GPR109A - cPLA2 - 髓鞘 - 认知级联反应提示了新的促智干预措施，例如给予聚乙二醇化犬尿氨酸酶，该酶催化色氨酸代谢产物犬尿氨酸（Kyn）生成AA；聚乙二醇化干扰素 - α；中枢和外周犬尿氨酸转氨酶抑制剂，它们可增加Kyn作为AA生成底物的可用性；以及迷走神经刺激。该级联反应预测了外源性GPR109A激动剂的促智活性，这些激动剂曾作为抗血脂异常药物被设计并进行了临床试验（未成功）。所提出的级联反应可能与认知障碍的发病机制有关。关于神经退行性疾病中AA的数据很少，所提出的级联反应需要在临床前和临床研究中进一步探索。
