Kynurenines and Multiple Sclerosis: The Dialogue between the Immune System and the Central Nervous System

Abstract

Multiple sclerosis is an inflammatory disease of the central nervous system, in which axonal transection takes place in parallel with acute inflammation to various, individual extents. The importance of the kynurenine pathway in the physiological functions and pathological processes of the nervous system has been extensively investigated, but it has additionally been implicated as having a regulatory function in the immune system. Alterations in the kynurenine pathway have been described in both preclinical and clinical investigations of multiple sclerosis. These observations led to the identification of potential therapeutic targets in multiple sclerosis, such as synthetic tryptophan analogs, endogenous tryptophan metabolites (e.g., cinnabarinic acid), structural analogs (laquinimod, teriflunomid, leflunomid and tranilast), indoleamine-2,3-dioxygenase inhibitors (1MT and berberine) and kynurenine-3-monooxygenase inhibitors (nicotinylalanine and Ro 61-8048). The kynurenine pathway is a promising novel target via which to influence the immune system and to achieve neuroprotection, and further research is therefore needed with the aim of developing novel drugs for the treatment of multiple sclerosis and other autoimmune diseases.

Keywords: indoleamine-2,3-dioxygenase; kynurenine pathway; multiple sclerosis.

Figure 1

Alterations of the KP in EAE and MS. Alterations in the kynurenine pathway in EAE and MS—this schematic picture summarizes the alterations of the different kynurenine metabolites and enzymes in the animal model and human disease based on the presently published data. For list of abbreviations see page 9.

Figure 2

Possible therapeutic targets in MS. Possible therapeutic targets in the kynurenine pathway—the figure displays the future drug candidates which are influencing the kynurenine pathway (molecules indicated in the frames) or have structural similarities (represented in dashed line boxes) with kynurenine metabolites.