（R，S）-氯胺酮代谢物（R，S）-去甲氯胺酮和（2S，6S）-羟基去甲氯胺酮增强雷帕霉素的哺乳动物靶点功能。
(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function.
作者信息
Paul Rajib K, Singh Nagendra S, Khadeer Mohammed, Moaddel Ruin, Sanghvi Mitesh, Green Carol E, O'Loughlin Kathleen, Torjman Marc C, Bernier Michel, Wainer Irving W
机构信息
From the Laboratory of Clinical Investigation (R.K.P., N.S.S., M.K., R.M., M.S., I.W.W.) and Translational Gerontology Branch (M.B.), National Institute on Aging, National Institutes of Health, Baltimore, Maryland; SRI Biosciences, SRI International, Menlo Park, California (C.E.G., K.O.); and Department of Anesthesiology, Cooper Medical School of Rowan University, Camden, New Jersey (M.C.T., I.W.W.).
出版信息
Anesthesiology. 2014 Jul;121(1):149-59. doi: 10.1097/ALN.0000000000000285.
BACKGROUND
Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown.
METHODS
Rats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined.
RESULTS
The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor.
CONCLUSIONS
The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.
背景
亚麻醉剂量的（R,S）-氯胺酮用于治疗神经性疼痛和抑郁症。在大鼠中，（R,S）-氯胺酮的抗抑郁作用与哺乳动物雷帕霉素靶蛋白（mTOR）的活性和功能增加有关；然而，（R,S）-氯胺酮会被广泛代谢，其代谢产物对mTOR信号增强的作用尚不清楚。
方法
给大鼠（每个时间点n = 3）注射（R,S）-氯胺酮、（R,S）-去甲氯胺酮和（2S,6S）-羟基去甲氯胺酮，并在20、30和60分钟后测定它们对mTOR通路的影响。用递增浓度的每种化合物处理PC-12嗜铬细胞瘤细胞（每个实验n = 3），并测定其对mTOR通路的影响。
结果
在大鼠前额叶皮质组织中，给予（R,S）-氯胺酮、（R,S）-去甲氯胺酮和（2S,6S）-羟基去甲氯胺酮60分钟后，mTOR及其下游靶点的磷酸化分别显著增加了约2.5倍、25倍和2倍以上（P < 0.05，方差分析）。在PC-12嗜铬细胞瘤细胞中，受试化合物以浓度依赖性方式激活mTOR通路，这导致丝氨酸消旋酶的表达显著升高，在0.05 nM（2S,6S）-羟基去甲氯胺酮、10 nM（R,S）-去甲氯胺酮和1000 nM（R,S）-氯胺酮作用下增加了约2倍。该效应的效力反映了受试化合物对α7-烟碱型乙酰胆碱受体的拮抗活性。
结论
数据表明，（R,S）-去甲氯胺酮和（2S,6S）-羟基去甲氯胺酮在体外和体内均具有强大的药理活性，并对亚麻醉剂量的（R,S）-氯胺酮产生的分子效应有贡献。结果表明，要确定（R,S）-氯胺酮的抗抑郁和镇痛作用的潜在机制，需要对母体化合物及其代谢产物进行全面研究。
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