GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice.
GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice.
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DOI：
10.1016/j.bbr.2015.10.060
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发表时间：
2016-02-15
影响因子：
2.7
通讯作者：
Meltzer HY
中科院分区：
文献类型：
--
作者：
Rajagopal L;Burgdorf JS;Moskal JR;Meltzer HY
GLYX-13（rapastinel）是一种四肽（Thr-Pro-Pro-Thr-amide），据报道，基于其N-甲基-d-天冬氨酸受体（NMDAR）甘氨酸位点功能性部分激动作用，在人体中具有快速作用的抗抑郁特性。氯胺酮是一种非竞争性NMDAR拮抗剂，也据报道具有速效抗抑郁特性，在啮齿动物和人类中产生认知障碍，而雷帕替奈据报道在啮齿动物中具有认知增强特性，而不损害人类的认知，尽管临床试验有限。本研究的目的是比较雷帕替奈和氯胺酮在啮齿动物和人类中用苯环己哌啶（PCP）（已知严重损害认知的另一种NMDAR非竞争性拮抗剂）处理的雄性C57 BL/6 J小鼠中在新物体识别（NOR）（陈述性记忆的量度）中的认知损害作用。注射用）分别显示急性或持续性NOR缺陷。急性静脉注射雷帕替奈（1.0 mg/kg）未诱导NOR缺陷。雷帕替奈预处理可显著预防急性氯胺酮诱导的NOR缺陷。Rapastinel（1.0 mg/kg，但不是0.3 mg/kg，iv）可显著逆转亚慢性氯胺酮和亚慢性PCP诱导的NOR缺陷。Rapastinel还增强了具有抗抑郁特性的非典型抗精神病药物鲁拉西酮恢复亚慢性氯胺酮处理小鼠的NOR。这些发现表明，与氯胺酮不同，雷帕替奈不会诱导小鼠的陈述性记忆缺陷，并且可以预防或逆转氯胺酮诱导的NOR缺陷。需要进一步研究以确定这些差异是否在氯胺酮和雷帕替奈作为速效抗抑郁药的临床使用期间转化，以及雷帕替奈作为抗精神病/抗抑郁药的添加治疗是否具有非离子效应。
GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-d-aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited. The goal of this study was to compare the cognitive impairing effects of rapastinel and ketamine in novel object recognition (NOR), a measure of declarative memory, in male C57BL/6J mice treated with phencyclidine (PCP), another NMDAR noncompetitive antagonist known to severely impair cognition, in both rodents and man. C57BL/6J mice given a single dose or subchronic ketamine (30 mg/kg. i.p.) showed acute or persistent deficits in NOR, respectively. Acute i.v. rapastinel (1.0 mg/kg), did not induce NOR deficit. Pre-treatment with rapastinel significantly prevented acute ketamine-induced NOR deficit. Rapastinel (1.0 mg/kg, but not 0.3 mg/kg, iv) significantly reversed both subchronic ketamine- and subchronic PCP-induced NOR deficits. Rapastinel also potentiated the atypical antipsychotic drug with antidepressant properties, lurasidone, to restore NOR in subchronic ketamine-treated mice. These findings indicate that rapastinel, unlike ketamine, does not induce a declarative memory deficit in mice, and can prevent or reverse the ketamine-induced NOR deficit. Further study is required to determine if these differences translate during clinical use of ketamine and rapastinel as fast acting antidepressant drugs and if rapastinel could have non-ionotropic effects as an add-on therapy with antipsychotic/antidepressant medications.