The kynurenine pathway and the brain: Challenges, controversies and promises

Abstract

Research on the neurobiology of the kynurenine pathway has suffered years of relative obscurity because tryptophan degradation, and its involvement in both physiology and major brain diseases, was viewed almost exclusively through the lens of the well-established metabolite serotonin. With increasing recognition that kynurenine and its metabolites can affect and even control a variety of classic neurotransmitter systems directly and indirectly, interest is expanding rapidly. Moreover, kynurenine pathway metabolism itself is modulated in conditions such as infection and stress, which are known to induce major changes in well-being and behaviour, so that kynurenines may be instrumental in the etiology of psychiatric and neurological disorders. It is therefore likely that the near future will not only witness the discovery of additional physiological and pathological roles for brain kynurenines, but also ever-increasing interest in drug development based on these roles. In particular, targeting the kynurenine pathway with new specific agents may make it possible to prevent disease by appropriate pharmacological or genetic manipulations. The following overview focuses on areas of kynurenine research which are either controversial, of major potential therapeutic interest, or just beginning to receive the degree of attention which will clarify their relevance to neurobiology and medicine. It also highlights technical issues so that investigators entering the field, and new research initiatives, are not misdirected by inappropriate experimental approaches or incorrect interpretations at this time of skyrocketing interest in the subject matter.

Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain

“…However, this notion is based on in vitro analysis of cellular responses to LPS or cytokine administration (Corona, et al 2010; Guillemin, et al 2003) (Chiarugi, et al 2001; Schwarcz and Stone 2017). Consistent with a recent report (Liu, et al 2017), we also observed activation of microglia in the hippocampus in response to SNI.…”

“…IDO1 initiates the metabolism of tryptophan into kynurenine (KYN). Kynurenine can be further converted to 3-hydroxy-kynurenine (3-HK) by kynurenine 3-monooxygenase (KMO), and ultimately transformed into quinolinic acid (QA) by kynureninase (KYNU) and 3-hydroxyanthralinic acid dioxygenase (HAAO) (Schwarcz and Stone 2017). Quinolinic acid is a neurotoxic N-methyl-D-aspartate receptor (NMDAR) agonist (Guillemin 2012; Santamaria and Rios 1993).…”

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

“…The kynurenine pathway is relatively less understood despite its dominant role in tryptophan catabolism. This pathway has been studied mainly in biochemistry and neurology, in the latter case as a source of catabolites contributing to psychogenic disease (Schwarcz, Stone, 2017). Biochemically, IDO and TDO control the rate-limiting first step in tryptophan catabolism leading to generation of the key enzyme co-factor nicotinamine adenine dinucleotide (NAD).…”

Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’

“…Historical studies of the kynurenine pathway of tryptophan catabolism have defined roles in neurological and immunological functions [7–9]. IDO1 is extrahepatic and inducible in many cell types by interferons and other diverse pro-inflammatory signals.…”