Kynurenine System and Multiple Sclerosis, Pathomechanism and Drug Targets with An Emphasis on Laquinimod

Abstract

Multiple sclerosis is a common chronic, disabling autoimmune neurological disease affecting mainly young adults. In its pathomechanism, neurodegenerative and acute inflammatory characteristics are both involved. Disease-modifying therapies aim to reduce relapse-rate and slow down the deterioration in neurological functions. The currently available therapies fail to exert neuroprotective effects and most of them are associated with potentially toxic side-effects, therefore, ongoing research aims to develop novel drug candidates to cover these therapeutic gaps. The kynurenine pathway has been implicated in both the physiological processes of the central nervous system and in the pathomechanism of several neurological disorders as well. Alterations of the kynurenine pathway metabolites have been detected in multiple sclerosis and a number of potential therapeutic targets related to this metabolic route have been already identified. Laquinimod is a quinoline carboxamide showing structural similarities with kynurenic acid, which proved to have beneficial effects on reduction of brain atrophy and disability progression. The kynurenine pathway is therefore a promising target for the development of future drugs for the treatment of autoimmune diseases such as multiple sclerosis.

Quantification of Plasma Kynurenine Metabolites Following One Bout of Sprint Interval Exercise

“…The pathway is tightly regulated by enzymes and several of its metabolites are neuroactive with tissue- and cell-specific effects. 1 Activation of the kynurenine pathway is implicated in a variety of disorders and diseases, including tick-borne encephalitis (TBE), 2 human immunodeficiency virus infection (HIV), 2,3 malaria, 4,5 system lupus erythematosus (SLE), 6,7 multiple sclerosis (MS), 8,9 cardiovascular disorder, 10 and diabetes. 11-13 Furthermore, activation of the kynurenine pathway is present in psychiatric disorders such as schizophrenia, 14,15 major depression, 16 bipolar disorder, 17,18 and suicidality.…”

Kynurenines in the Pathogenesis of Multiple Sclerosis: Therapeutic Perspectives

“…Estimations put its concentration in the CNS around 13% of the blood concentration [282]. It has a half-life of approximately 80 h and it is metabolized by cytochrome P450 (CYP 450) enzyme family [279].…”

“…It reduces the number of CD4 + dendritic cells and through it, the amount of Th1 and Th17 cells, while increasing the number of Treg cells [288]. Laquinimod was also shown to decrease microglial activation, leading to reduced axonal damage [279]. A recent study has concluded that laquinimod can induce remyelination through the protection of oligodendrocyte progenitors during differentiation [289].…”

“…In spite of these strengths, as described above, it was not approved by the CHMP. However, there are some data that laquinimod may be a beneficial add-on therapy in the future for MS. Additionally, as studies are still ongoing in other diseases-e.g., Huntington's disease-and there are strong pre-clinical results in hemorrhagic stroke, laquinimod may still become an important neuroprotective therapy in the near future [279,296].…”

“…Laquinimod (or N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide) ( Figure 2 ) was first synthesized as a structural variant of roquinimex, an initially promising, but later retracted drug for MS (due to severe adverse effects) [ 278 , 279 ]. It displays a remarkable structural similarity to kynurenines, with proposed immunomodulatory and neuroprotective attributes, rather than immunosuppressive effects.…”