Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration.
Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration.
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DOI：
10.1038/s41398-022-01941-x
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发表时间：
2022-05-02
影响因子：
6.8
通讯作者：
Zarate, Carlos A., Jr.
中科院分区：
文献类型：
--
作者：
Moaddel, Ruin;Zanos, Panos;Farmer, Cristan A.;Kadriu, Bashkim;Morris, Patrick J.;Lovett, Jacqueline;Acevedo-Diaz, Elia E.;Cavanaugh, Grace W.;Yuan, Peixiong;Yavi, Mani;Thomas, Craig J.;Park, Lawrence T.;Ferrucci, Luigi;Gould, Todd D.;Zarate, Carlos A., Jr.
亚麻醉剂量外消旋（R，S）-氯胺酮（氯胺酮）在重度抑郁症（MDD）和双相情感障碍（BD）中产生快速，稳健和持续的抗抑郁作用，并且还显示出有效治疗神经性疼痛，复杂区域疼痛综合征和创伤后应激障碍（PTSD）。然而，迄今为止，其作用机制仍不清楚。临床前研究发现，氯胺酮的主要循环代谢物（2 R，6 R; 2S，6S）-羟基去甲氯胺酮（HNK）具有与氯胺酮相似的抗抑郁作用。为了帮助确定（2 R，6 R）-HNK如何促进氯胺酮的作用机制，对接受40分钟氯胺酮输注（0.5 mg/kg）的9名健康志愿者的血浆和CSF进行了探索性、靶向代谢组学分析。在接受10 mg/kg氯胺酮、10 mg/kg（2 R，6 R）-HNK或生理盐水的小鼠中进行血浆、海马和下丘脑中的平行靶向代谢组学分析。氯胺酮和（2 R，6 R）-HNK均影响与炎症状态相关的多个通路.此外，健康人类志愿者和/或研究的小鼠组的几个变化是独特的，表明不同的途径可能差异性地参与氯胺酮在小鼠和人类中的作用。发现氯胺酮和/或（2 R，6 R）-HNK对血浆和CSF中的人代谢组和研究小鼠组的作用一致的作用机制包括LAT 1、IDO 1、NAD+、一氧化氮（NO）信号通路和鞘脂变阻器。
Subanesthetic-dose racemic (R,S)-ketamine (ketamine) produces rapid, robust, and sustained antidepressant effects in major depressive disorder (MDD) and bipolar disorder (BD) and has also been shown to effectively treat neuropathic pain, complex regional pain syndrome, and post-traumatic stress disorder (PTSD). However, to date, its mechanism of action remains unclear. Preclinical studies found that (2 R,6 R;2 S,6 S)-hydroxynorketamine (HNK), a major circulating metabolite of ketamine, elicits antidepressant effects similar to those of ketamine. To help determine how (2 R,6 R)-HNK contributes to ketamine’s mechanism of action, an exploratory, targeted, metabolomic analysis was carried out on plasma and CSF of nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg). A parallel targeted metabolomic analysis in plasma, hippocampus, and hypothalamus was carried out in mice receiving either 10 mg/kg of ketamine, 10 mg/kg of (2 R,6 R)-HNK, or saline. Ketamine and (2 R,6 R)-HNK both affected multiple pathways associated with inflammatory conditions. In addition, several changes were unique to either the healthy human volunteers and/or the mouse arm of the study, indicating that different pathways may be differentially involved in ketamine’s effects in mice and humans. Mechanisms of action found to consistently underlie the effects of ketamine and/or (2 R,6 R)-HNK across both the human metabolome in plasma and CSF and the mouse arm of the study included LAT1, IDO1, NAD+, the nitric oxide (NO) signaling pathway, and sphingolipid rheostat.
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DOI：
10.1093/gerona/gly100
发表时间：
2019-01-01
影响因子：
5.1
作者：
Gonzalez-Freire, Marta;Moaddel, Ruin;Semba, Richard D.
通讯作者：
Semba, Richard D.
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
DOI：
10.1152/ajpcell.1996.270.2.c636
发表时间：
1996-02-01
影响因子：
5.5
作者：
Denson, DD;Worrell, RT;Eaton, DC
通讯作者：
Eaton, DC
影响因子：
64.5
作者：
Casarotto PC;Girych M;Fred SM;Kovaleva V;Moliner R;Enkavi G;Biojone C;Cannarozzo C;Sahu MP;Kaurinkoski K;Brunello CA;Steinzeig A;Winkel F;Patil S;Vestring S;Serchov T;Diniz CRAF;Laukkanen L;Cardon I;Antila H;Rog T;Piepponen TP;Bramham CR;Normann C;Lauri SE;Saarma M;Vattulainen I;Castrén E
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Castrén E
影响因子：
4
作者：
Dobos, Nikoletta;de Vries, Erik F. J.;Eisel, Ulrich L. M.
通讯作者：
Eisel, Ulrich L. M.