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Related Experiment Video

Updated: Apr 26, 2026

A High-performance Liquid Chromatography Measurement of Kynurenine and Kynurenic Acid: Relating Biochemistry to Cognition and Sleep in Rats
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Reduction of brain kynurenic acid improves cognitive function.

Rouba Kozak1, Brian M Campbell2, Christine A Strick3

  • 1Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139, rouba.kozak@pfizer.com.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|August 8, 2014
PubMed
Summary

Elevated kynurenic acid (KYNA) in schizophrenia may cause cognitive issues. Inhibiting its production with PF-04859989 improved cognitive performance in animal models, suggesting a therapeutic target.

Keywords:
KAT IIcognitionkynurenic acidl-kynurenineschizophreniaworking memory

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Area of Science:

  • Neuroscience
  • Psychiatry
  • Pharmacology

Background:

  • Kynurenic acid (KYNA) is elevated in schizophrenia patients, potentially causing cognitive impairments via glutamate hypofunction.
  • KYNA may antagonize NMDA receptors and modulate nicotinic acetylcholine receptors, contributing to schizophrenia symptoms.

Purpose of the Study:

  • To investigate the role of endogenous KYNA in brain function and behavior.
  • To evaluate PF-04859989, a novel inhibitor of kynurenine aminotransferase II (KAT II), for its ability to reduce brain KYNA levels and improve cognitive function.

Main Methods:

  • Developed and utilized PF-04859989, a brain-penetrant KAT II inhibitor.
  • Administered PF-04859989 systemically in rats, rodents, and nonhuman primates.
  • Assessed effects on brain KYNA levels, auditory gating, sustained attention, working memory, and spatial memory.

Main Results:

  • PF-04859989 dose-dependently reduced brain KYNA levels in rats.
  • The inhibitor prevented amphetamine- and ketamine-induced disruptions in auditory gating and attention.
  • PF-04859989 improved performance in working memory and spatial memory tasks in various animal models.

Conclusions:

  • Endogenous KYNA significantly impacts cognitive function.
  • Inhibition of KAT II and subsequent reduction of brain KYNA levels represent a promising therapeutic strategy for improving cognitive deficits in schizophrenia.