title: Reduction of brain kynurenic acid improves cognitive function.
abstract: The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the α7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine- and ketamine-induced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia.
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139, rouba.kozak@pfizer.com.
authors.forename: Rouba
authors.initials: R
authors.lastname: Kozak
authors.affiliation: Lundbeck Research US, Paramus, New Jersey 07652, and.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Campbell
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Strick
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Weldon
authors.initials: W
authors.lastname: Horner
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: William E
authors.initials: WE
authors.lastname: Hoffmann
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Tamas
authors.initials: T
authors.lastname: Kiss
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Chapin
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Dina
authors.initials: D
authors.lastname: McGinnis
authors.affiliation: Departments of Psychiatry and VA Connecticut Healthcare System, West Haven, Connecticut 06519.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Abbott
authors.affiliation: Departments of Psychiatry and VA Connecticut Healthcare System, West Haven, Connecticut 06519.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Roberts
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Kari
authors.initials: K
authors.lastname: Fonseca
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Victor
authors.initials: V
authors.lastname: Guanowsky
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Damon A
authors.initials: DA
authors.lastname: Young
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Seymour
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Amy
authors.initials: A
authors.lastname: Dounay
authors.affiliation: Comparative Medicine, Yale School of Medicine, New Haven, Connecticut 06510.
authors.forename: Mihaly
authors.initials: M
authors.lastname: Hajos
authors.affiliation: Departments of Psychiatry and VA Connecticut Healthcare System, West Haven, Connecticut 06519.
authors.forename: Graham V
authors.initials: GV
authors.lastname: Williams
authors.affiliation: Departments of Psychiatry and VA Connecticut Healthcare System, West Haven, Connecticut 06519.
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Castner
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D003071:Cognition / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005072:Evoked Potentials, Auditory / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007736:Kynurenic Acid / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000134:cerebrospinal fluid* / Q000473:pathology*; D014851:Wakefulness
chemical_list: D004791:Enzyme Inhibitors; C583657:PF-04859989; D011720:Pyrazoles; D007736:Kynurenic Acid
keywords: KAT II; cognition; kynurenic acid; l-kynurenine; schizophrenia; working memory
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