Novel Activity of Oral Hypoglycemic Agents Linked with Decreased Formation of Tryptophan Metabolite, Kynurenic Acid

Abstract

Kynurenic acid is a tryptophan (Trp) metabolite formed along the kynurenine (KYN) pathway in the brain and in peripheral tissues. The disturbed formation of kynurenic acid, which targets glutamate-mediated neurotransmission, GPR35, and aryl hydrocarbon receptors of immune or redox status, was implicated in the development of neuropsychiatric and metabolic disorders among others. Kynurenic acid exerts neuroprotective and immunomodulatory effects, yet its high brain levels may negatively impact cognition. Changes in the Trp–KYN pathway are also linked with the pathogenesis of diabetes mellitus, which is an established risk factor for cardiovascular and neurological diseases or cognitive deficits. Here, the effects of metformin and glibenclamide on the brain synthesis of kynurenic acid were evaluated. Acute exposure of rat cortical slices in vitro to either of the drugs reduced kynurenic acid production de novo. Glibenclamide, but not metformin, inhibited the activity of kynurenic acid biosynthetic enzymes, kynurenine aminotransferases (KATs) I and II, in semi-purified cortical homogenates. The reduced availability of kynurenic acid may be regarded as an unwanted effect, possibly alleviating the neuroprotective action of oral hypoglycemic agents. On the other hand, considering that both compounds ameliorate the cognitive deficits in animal and human studies and that high brain kynurenic acid may hamper learning and memory, its diminished synthesis may improve cognition.