UPF 648, a Selective KMO Inhibitor, Attenuates Psychomotor and Cognitive Impairment in Chronic Kidney Disease.

Abstract

Kynurenine-3-monooxygenase (KMO), a key enzyme in the kynurenine pathway (KP) of tryptophan metabolism, converts kynurenine into the neurotoxic intermediate quinolinic acid (QA). QA, an N-methyl-d-aspartate (NMDA) receptor agonist, increases glutamate release and inhibits its reuptake, resulting in excitotoxic cell death in the hippocampus and striatum. Plasma metabolomics study exhibited KP metabolites as the most altered pathway in patients with chronic kidney disease (CKD). Recently, QA was linked to the kidney-brain axis as one of the major neurotoxins responsible for cognitive impairment in advanced CKD stages. Various preclinical models are being tested to explore different intermediates of KP that can be targeted to ameliorate the central nervous system (CNS) complications of CKD. In this study, an adenine-induced CKD model was developed in C57BL/6 mice, where UPF 648, a selective KMO inhibitor, was administered to observe the changes in KP metabolites in the hippocampus. Treatment with UPF 648 did not alter kidney function or morphology in CKD. KMO inhibition led to decreased plasma QA levels and reduced levels of pro-inflammatory cytokine interleukin-1-β (IL-1β). UPF 648 treatment in CKD ameliorated the characteristic symptoms of motor dysfunction, anxiety, depression, and hippocampus-dependent memory. Important markers for neuronal survival and plasticity through the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TRKB)-cAMP-responsive element binding protein 1 (CREB1) pathway were upregulated in the hippocampus after KMO inhibition. In conclusion, KMO inhibition can be an exciting target to attenuate the neuropsychiatric burden of advanced stages in CKD.