The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications

• Published in: Journal of Neural Transmission 2012-02, Vol.119 (2), p.225-234
• Main Authors: Füvesi, Judit, Rajda, Cecilia, Bencsik, Krisztina, Toldi, József, Vécsei, László
• Format: Article
• Language: English
• Subjects: Amino acids; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Basic Neurosciences; Bioavailability; Blood-brain barrier; Brain; Drugs; Enzymes; Genetics and Immunology - Review article; Humans; Inflammation; Kynurenic acid; Kynurenine - administration & dosage; Kynurenine - physiology; Medicine; Medicine & Public Health; Metabolites; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - pathology; Multiple Sclerosis - physiopathology; Neural Pathways - drug effects; Neural Pathways - physiology; Neural Pathways - physiopathology; Neurodegenerative diseases; Neurology; Neuroprotection; Neurosciences; organic acids; prodrugs; Prodrugs - administration & dosage; Prodrugs - therapeutic use; Protein transport; Psychiatry; Tryptophan
• ISSN: 0300-9564; 1435-1463
• DOI: 10.1007/s00702-012-0765-3

Tryptophan is one of the essential amino acids, 80% of which is catabolised in the extrahepatic tissues by indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway. Metabolites along the kynurenine pathway have been implicated to play a role in the pathomechanism of neuroinflammatory and neurodegenerative disorders. Changes in the concentration levels of kynurenines can shift the balance to pathological conditions. The ability to influence the metabolism towards the neuroprotective branch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA) synthesis, may be one option in preventing neurodegenerative diseases. Three potential therapeutic strategies could be feasible to develop drugs to live up to expectations: (1) chemically related drugs with better bioavailability and higher affinity to the binding sites of excitatory receptors; (2) prodrugs of KYNA, which easily cross the blood–brain barrier combined with an inhibitor of organic acid transport for enhancement of the brain KYNA concentration; (3) inhibitors of enzymes of the kynurenine pathway. In this review, we focus on aspects of the pathomechanism and therapeutic possibilities of amyotrophic lateral sclerosis and multiple sclerosis that may be influenced by kynurenines.