Determination of Diffusion Kinetics of Ketamine in Brain Tissue: Implications for in vitro Mechanistic Studies of Drug Actions.
Determination of Diffusion Kinetics of Ketamine in Brain Tissue: Implications for in vitro Mechanistic Studies of Drug Actions.
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DOI：
10.3389/fnins.2021.678978
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发表时间：
2021
影响因子：
4.3
通讯作者：
Yuan LL
中科院分区：
文献类型：
--
作者：
Geiger Z;VanVeller B;Lopez Z;Harrata AK;Battani K;Wegman-Points L;Yuan LL
氯胺酮作为全身麻醉剂已经使用了50多年，主要通过阻断大脑中的N-甲基-D-天冬氨酸受体起作用。最近的研究表明，氯胺酮在亚麻醉剂量下给药时也可作为一种强效和速效的抗抑郁药。然而，这种效应背后的确切机制仍不清楚。我们检查了氯胺酮在脑组织中的扩散特性，以确定其在与氯胺酮的抗抑郁作用相关的体外研究中的作用。将成年小鼠的脑切片暴露于含1.17 μM盐酸氯胺酮的人工脑脊液（aCSF）中不同时间。然后通过串联高效液相色谱-质谱法测量每个切片内氯胺酮的量，以表征氯胺酮随时间扩散到脑组织中。我们使用时间常数τ = 6.59 min的单指数函数成功模拟了氯胺酮向脑组织中的扩散。然后将该曲线与一维扩散模型进行比较，得出氯胺酮向脑组织中扩散的扩散系数约为0.12 cm 2·s-1。氯胺酮的脑：aCSF分配系数测定为约2.76。我们的研究结果表明，氯胺酮的扩散性能有显着的影响，在体外实验期间脑组织内实现的药物浓度。该信息对于确定体外切片制备所需的氯胺酮浓度以准确反映负责其抗抑郁作用的体内剂量至关重要。
Ketamine has been in use for over 50 years as a general anesthetic, acting primarily through blockade of N-methyl-D-aspartate receptors in the brain. Recent studies have demonstrated that ketamine also acts as a potent and rapid-acting antidepressant when administered at sub-anesthetic doses. However, the precise mechanism behind this effect remains unclear. We examined the diffusion properties of ketamine in brain tissue to determine their effects in in vitro studies related to the antidepressant action of ketamine. Brain slices from adult mice were exposed to artificial cerebrospinal fluid (aCSF) containing ∼17 μM ketamine HCl for varying amounts of time. The amount of ketamine within each slice was then measured by tandem high-performance liquid chromatography – mass spectrometry to characterize the diffusion of ketamine into brain tissue over time. We successfully modeled the diffusion of ketamine into brain tissue using a mono-exponential function with a time constant of τ = 6.59 min. This curve was then compared to a one-dimensional model of diffusion yielding a diffusion coefficient of approximately 0.12 cm2⋅s–1 for ketamine diffusing into brain tissue. The brain:aCSF partition coefficient for ketamine was determined to be approximately 2.76. Our results suggest that the diffusion properties of ketamine have a significant effect on drug concentrations achieved within brain tissue during in vitro experiments. This information is vital to determine the ketamine concentration necessary for in vitro slice preparation to accurately reflect in vivo doses responsible for its antidepressant actions.
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影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
9.8
作者：
Gredell, JA;Turnquist, PA;Pearce, RA
通讯作者：
Pearce, RA
影响因子：
3.8
作者：
Zou, Xiaoju;Patterson, Tucker A.;Wang, Cheng
通讯作者：
Wang, Cheng
影响因子：
3.5
作者：
Zhao, Cuiping;Wang, Lang;Yuan, Li-Lian
通讯作者：
Yuan, Li-Lian