Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts 02139,
Lundbeck Research US, Paramus, New Jersey 07652, and.
J Neurosci. 2014 Aug 6;34(32):10592-602. doi: 10.1523/JNEUROSCI.1107-14.2014.
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.
在精神分裂症患者中观察到的犬尿氨酸（KYNA）升高可能有助于谷氨酸功能低下引起的核心症状，包括认知障碍。尽管 KYNA 水平的升高会降低兴奋性神经传递，但 KYNA 被提议作为谷氨酸 NMDA 受体（NMDAR）甘氨酸部位的内源性拮抗剂，以及作为α7 烟碱型乙酰胆碱受体的负变构调节剂。在精神分裂症患者的 CSF 和死后大脑中，KYNA 水平升高，这些升高的 KYNA 水平可能导致 NMDAR 功能低下，以及与该疾病相关的认知缺陷和阴性症状。然而，由于缺乏药理学工具，内源性产生的 KYNA 对大脑功能和行为的影响了解较少。为了解决这个问题，我们鉴定出 PF-04859989，这是一种犬尿氨酸氨基转移酶 II（KAT II）的脑可渗透抑制剂，KAT II 是负责大多数大脑 KYNA 合成的酶。在大鼠中，PF-04859989 的全身给药剂量依赖性地将大脑 KYNA 降低至基础水平的 28%以下，并预防安非他命和氯胺酮诱导的听觉门控破坏和在持续注意力任务中的表现改善。它还预防了氯胺酮诱导的啮齿动物和非人类灵长类动物在工作记忆任务和空间记忆任务中的表现破坏，分别。这些发现共同支持了以下假设，即内源性 KYNA 影响认知功能，并且抑制 KAT II，以及随后降低内源性脑 KYNA 水平，在被认为与精神分裂症相关的条件下改善认知表现。
