Laboratory of Neuropharmacology, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), University of the Balearic Islands (UIB), and Institut d'investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain.
Laboratory of Neuropharmacology, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), University of the Balearic Islands (UIB), and Institut d'investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jan 10;88:121-131. doi: 10.1016/j.pnpbp.2018.07.006. Epub 2018 Jul 10.
Ketamine (KET) is an antidepressant and hypnotic drug acting as an antagonist at excitatory NMDA glutamate receptors. The working hypothesis postulated that KET-induced sleep in mice results in dysregulation of mitogen-activated protein kinases (MAPK) MEK-ERK sequential phosphorylation and upregulation of survival p-FADD and other neuroplastic markers in brain. Low (5-15 mg/kg) and high (150 mg/kg) doses of KET on target proteins were assessed by Western immunoblot in mouse brain cortex. During the time course of KET (150 mg/kg)-induced sleep (up to 50 min) p-MEK was increased (up to +79%) and p-ERK decreased (up to -46%) indicating disruption of MEK to ERK signal. Subhypnotic KET (5-15 mg/kg) also revealed uncoupling of p-MEK (+13-81%) to p-ERK (unchanged content). KET did not alter contraregulatory MAPK mechanisms such as inactivated p-MEK1 (ERK dampening) and phosphatases MKP1/2/3 (ERK dephosphorylation). As other relevant findings, KET (5, 15 and 150 mg/kg) upregulated p-FADD in a dose-dependent manner, and for the hypnotic dose the effect paralleled the time course of sleep which resulted in increased p-FADD/FADD ratios. KET (150 mg/kg) also increased NF-κΒ and PSD-95 neuroplastic markers. Flumazenil (a neutral allosteric antagonist at GABA receptor) prolonged KET sleep and blocked p-MEK upregulation, indicating the involvement of this receptor as a negative modulator. SL-327 (a MEK inhibitor) augmented KET sleep, further indicating the relevance of reduced p-ERK1/2 in KET-induced hypnosis. These findings suggest that hypnotic and subhypnotic doses of KET inducing uncoupling of p-MEK to p-ERK signal and regulation of p-ERK (downregulation) and p-FADD (upregulation) may participate in the expression of some of its adverse effects (e.g. amnesia, dissociative effects).
氯胺酮（KET）是一种抗抑郁药和催眠药，作为兴奋性 NMDA 谷氨酸受体的拮抗剂。工作假说推测，氯胺酮诱导的小鼠睡眠导致丝裂原激活的蛋白激酶（MAPK）MEK-ERK 顺序磷酸化失调，并上调脑中存活的 p-FADD 和其他神经可塑性标志物。通过 Western 免疫印迹法评估了小鼠大脑皮质中目标蛋白上的低（5-15mg/kg）和高（150mg/kg）剂量的 KET。在氯胺酮（150mg/kg）诱导的睡眠（长达 50 分钟）过程中，p-MEK 增加（高达+79%），p-ERK 减少（高达-46%），表明 MEK 到 ERK 信号的中断。亚催眠剂量的 KET（5-15mg/kg）也显示出 p-MEK 的解偶联（+13-81%）到 p-ERK（内容不变）。氯胺酮没有改变反向调节的 MAPK 机制，例如失活的 p-MEK1（ERK 衰减）和磷酸酶 MKP1/2/3（ERK 去磷酸化）。作为其他相关发现，氯胺酮（5、15 和 150mg/kg）以剂量依赖性方式上调 p-FADD，对于催眠剂量，该作用与睡眠的时间过程平行，导致 p-FADD/FADD 比值增加。氯胺酮（150mg/kg）还增加了 NF-κΒ 和 PSD-95 神经可塑性标志物。氟马西尼（GABA 受体的中性变构拮抗剂）延长了氯胺酮的睡眠并阻断了 p-MEK 的上调，表明该受体作为负调节剂的参与。SL-327（MEK 抑制剂）增强了氯胺酮的睡眠，进一步表明在氯胺酮诱导的催眠作用中 p-ERK1/2 的减少具有相关性。这些发现表明，催眠和亚催眠剂量的氯胺酮诱导 p-MEK 与 p-ERK 信号的解偶联以及 p-ERK（下调）和 p-FADD（上调）的调节可能参与了其一些不良反应（例如，健忘症、分离效应）的表达。
