Kynurenic acid in neurodegenerative disorders—unique neuroprotection or double‐edged sword?

Abstract

Aims The family of kynurenine pathway (KP) metabolites includes compounds produced along two arms of the path and acting in clearly opposite ways. The equilibrium between neurotoxic kynurenines, such as 3‐hydroxykynurenine (3‐HK) or quinolinic acid (QUIN), and neuroprotective kynurenic acid (KYNA) profoundly impacts the function and survival of neurons. This comprehensive review summarizes accumulated evidence on the role of KYNA in Alzheimer's, Parkinson's and Huntington's diseases, and discusses future directions of potential pharmacological manipulations aimed to modulate brain KYNA. Discussion The synthesis of specific KP metabolites is tightly regulated and may considerably vary under physiological and pathological conditions. Experimental data consistently imply that shift of the KP to neurotoxic branch producing 3‐HK and QUIN formation, with a relative or absolute deficiency of KYNA, is an important factor contributing to neurodegeneration. Targeting specific brain regions to maintain adequate KYNA levels seems vital; however, it requires the development of precise pharmacological tools, allowing to avoid the potential cognitive adverse effects. Conclusions Boosting KYNA levels, through interference with the KP enzymes or through application of prodrugs/analogs with high bioavailability and potency, is a promising clinical approach. The use of KYNA, alone or in combination with other compounds precisely influencing specific populations of neurons, is awaiting to become a significant therapy for neurodegenerative disorders.

The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases

“…Manipulation of the kynurenine pathway away from neurotoxic quinolinic acid and towards the neuroprotective NMDA antagonist, kynurenic acid, is a possible therapeutic focus [ 100 ]. Nicotinylalanine has been shown to be an inhibitor of kynurenine hydroxylase, which results in decreased production of quinolinic acid, but its protective effect is questionable [ 101 ]. Therapeutic efforts have also focused on antioxidants, which have been shown to provide protection against the pro-oxidant properties of quinolinic acid [ 74 ].…”

Memory Enhancement with Kynurenic Acid and its Mechanisms in Neurotransmission

“…A shift in the balance of the Trp-KYN metabolic system toward the relative excess of neurotoxic molecules such as quinolinic acid (QUIN) has been implicated in the pathomechanisms of several neurological, neurodegenerative and psychiatric disorders, including epilepsy, Huntington's (HD), Parkinson's (PD), AD, and depressive disorder. Intervention to restore the balance or KYNA supplementation in the brain has been widely linked to neuroprotective actions in animal models of various diseases [102,103]. However, the influence of the KYN metabolites on certain diseases remains controversial.…”

A Glimpse of Molecular Biomarkers in Huntington’s Disease

“…The kynurenine pathway is involved in the oxidative metabolism of tryptophan in microglia that generates metabolites such as 3-hydroxykinurine (3-HK) and its downstream product quinolinic acid (QUIN), which exert potent neurotoxic effects by inducing excitoxicity through NMDA receptors and increasing the production of reactive oxygen species (ROS) that induces lipid peroxidation, among other actions [ 99 ]. In contrast, another metabolite of the same pathway, kynurenic acid (KYNA), has neuroprotective effects, and manipulation of the kynurenine pathway to produce KYNA instead of 3-HK and QUIN has been postulated as a potential therapeutic approach [ 100 ]. However, the presence of these three metabolites in CSF has apparently no prognostic value, as no differences were observed between controls, premanifest and manifest patients [ 101 ].…”