N-Acetylcysteine Inhibits Kynurenine Aminotransferase II
T Blanco-Ayala1, K V Sathyasaikumar1, J D Uys2
1Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
Neuroscience
|August 10, 2020
Summary
N-acetylcysteine (NAC) reduces kynurenic acid (KYNA) production in the brain by inhibiting the kynurenine aminotransferase II (KAT II) enzyme. This finding suggests NAC may improve cognitive function by lowering KYNA levels.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Kynurenic acid (KYNA), a tryptophan metabolite, influences cognitive processes by interacting with nicotinic and NMDA receptors.
- Kynurenine aminotransferase II (KAT II) is crucial for synthesizing KYNA in the brain, making it a therapeutic target for cognitive enhancement.
- N-acetylcysteine (NAC) is a pro-cognitive drug thought to work by increasing brain glutathione (GSH) levels.
Purpose of the Study:
- To investigate the mechanism by which N-acetylcysteine (NAC) exerts its pro-cognitive effects.
- To determine if NAC inhibits KAT II activity and reduces kynurenic acid (KYNA) synthesis in the brain.
Main Methods:
- Assessed KAT II inhibition by NAC and GSH in rat and human brain homogenates and recombinant human KAT II.
- Measured KYNA formation in rat brain slices and in vivo using microdialysis in rats.
- Investigated the effect of NAC on S-glutathionylation of KAT II.
Main Results:
- NAC, but not GSH, inhibited KAT II activity and KYNA formation in brain homogenates and slices.
- NAC acted as a competitive inhibitor of recombinant human KAT II.
- In vivo, NAC administration significantly reduced KYNA neosynthesis in the rat prefrontal cortex.
Conclusions:
- N-acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), reducing cerebral kynurenic acid (KYNA) production.
- These findings suggest that NAC's neurobiological effects, including pro-cognitive efficacy, may be partly mediated by the inhibition of KYNA synthesis.
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