Anthranilic Acid-G-Protein Coupled Receptor109A-Cytosolic Phospholipase A2-Myelin-Cognition Cascade: A New Target for the Treatment/Prevention of Cognitive Impairment in Schizophrenia, Dementia, and Aging

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.