Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders.

Abstract:

:The kynurenine pathway constitutes the main route of tryptophan degradation and generates the production of several neuroactive compounds; quinolinic acid is an excitotoxic NMDA receptor agonist, 3-hydroxykynurenine is a free-radical generator and kynurenic acid (KYNA) is an antagonist at glutamate and nicotinic receptors. In low micromolar concentrations, KYNA blocks the glycine site of the NMDA receptor and the nicotinic alpha(7) acetylcholine receptor. Knowledge regarding kynurenine metabolites and their involvement in neurophysiological processes has increased dramatically in recent years. In particular, endogenous KYNA appears to tightly control firing of midbrain dopamine neurons and to be involved in cognitive functions. Thus, decreased endogenous levels of rat brain KYNA have been found to reduce firing of these neurons, and mice with a targeted deletion of kynurenine aminotransferase II display low endogenous brain KYNA levels concomitant with an increased performance in cognitive tests. It is also suggested that kynurenines participate in the pathophysiology of psychiatric disorders. Thus, elevated levels of KYNA have been found in the CSF as well as in the post-mortem brain of patients with schizophrenia. Advantages in understanding how kynurenines can be pharmacologically manipulated may provide new possibilities in the treatment of psychiatric disorders, such as schizophrenia.

journal_name

CNS Drugs

journal_title

CNS drugs

authors

Erhardt S,Olsson SK,Engberg G

doi

10.2165/00023210-200923020-00001

subject

Has Abstract

pub_date

2009-01-01 00:00:00

pages

91-101

issue

2

eissn

1172-7047

issn

1179-1934

pii

1

journal_volume

23

pub_type

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