Chronic increases in brain levels of kynurenic acid (KYNA) in schizophrenia patients are thought to contribute to impaired cognitive function. Here, the authors identify PF-04859989, the first brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II) — the enzyme responsible for brain KYNA synthesis — and demonstrate it to improve cognitive performance under schizophrenic conditions. In rats, systemic PF-04859989 reduced brain KYNA to 28% of basal levels, and prevented amphetamine- and ketamine-induced disruption of auditory gating. The KAT II inhibitor also prevented ketamine-induced impairment of attentional and working memory processes in rodents and non-human primates, respectively.
References
Kozak, R. et al. Reduction of brain kynurenic acid improves cognitive function. J. Neuroscience 34, 10592–10602 (2014)
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Crunkhorn, S. Enzyme inhibitor improves cognitive function. Nat Rev Drug Discov 13, 726 (2014). https://doi.org/10.1038/nrd4452
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DOI: https://doi.org/10.1038/nrd4452