The kynurenine pathway in neurodegenerative diseases: mechanistic and therapeutic considerations

J Neurol Sci. 2012 Dec 15;323(1-2):1-8. doi: 10.1016/j.jns.2012.08.005. Epub 2012 Aug 29.

Abstract

The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, consists of many metabolites including kynurenic acid (KYNA), quinolinic acid (QUIN), 3-hydroxykynurenine (3-HK) and picolinic acid (PIC). The former two are neuroactive, while the latter two are molecules with pro-oxidants and antioxidants properties. These agents are considered to be involved in aging and numerous neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Several studies have demonstrated that altered kynurenine metabolism plays an important role in the pathogenesis of this group of diseases. The important metabolites and key enzymes show significant importance in those disorders. Both analogs of the neuroprotective metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic compounds may have potential therapeutic significance. In this review we discuss the mechanistic and therapeutic considerations of KP in aging and the main neurodegenerative diseases and review the updated knowledge in this therapeutic field.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aging / metabolism
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / prevention & control
  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Huntington Disease / drug therapy
  • Huntington Disease / metabolism
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Inflammation / metabolism
  • Kynurenic Acid / antagonists & inhibitors
  • Kynurenic Acid / metabolism
  • Kynurenine / analogs & derivatives
  • Kynurenine / metabolism*
  • Kynurenine / pharmacology
  • Kynurenine / therapeutic use
  • Microglia / metabolism
  • Molecular Targeted Therapy*
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / prevention & control
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Neurotoxins / metabolism
  • Parkinson Disease / drug therapy
  • Parkinson Disease / metabolism
  • Parkinson Disease / prevention & control
  • Quinolinic Acid / antagonists & inhibitors
  • Quinolinic Acid / metabolism
  • Receptors, G-Protein-Coupled / drug effects
  • Receptors, G-Protein-Coupled / physiology
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Tryptophan / metabolism

Substances

  • Enzyme Inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Neuroprotective Agents
  • Neurotoxins
  • Receptors, G-Protein-Coupled
  • Receptors, N-Methyl-D-Aspartate
  • Kynurenine
  • 4-chlorokynurenine
  • Tryptophan
  • Quinolinic Acid
  • Kynurenic Acid