Qin Yu, Guo Xinlei, Song Wenyue, Liang Zehuai, Wang Yahui, Feng Dan, Yang Yiru, Li Mingxing, Gao Mingqi
School of Pharmacy, China Medical University, Shenyang 110122, China.
School of Pharmacy, China Medical University, Shenyang 110122, China.
Mol Cell Neurosci. 2023 Mar;124:103821. doi: 10.1016/j.mcn.2023.103821. Epub 2023 Feb 10.
As a non-competitive N-methyl d-aspartate receptor antagonist, ketamine exerts rapid-onset and long-lasting antidepressant effects on depression, but some side effects limit its use. To identify a safer compound that may provide similar antidepressant effects, here we investigated whether CP-101,606, a selective NR2B receptor inhibitor, provides similar antidepressant effects and explored its underlying mechanisms.
To mimic depressive-like behavior, mice were subjected to chronic unpredictable mild stress (CUMS) for 21 days. Mice were treated with CP-101,606 at 10, 20, and 40 mg/kg doses for 7, 14, and 21 days, respectively, followed by a sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). Western blot analysis was performed on several targets (mTOR, p-mTOR, p70S6K, p-p70S6K, PSD-95, and GluA1), along with immunohistochemistry (GluA1) and immunofluorescence (p-mTOR) assays, using hippocampal tissue.
CP-101,606 at 20 and 40 mg/kg doses for 7 and 14 days and fluoxetine 10 mg/kg and CP-101606 20 mg/kg for 21 days ameliorated depression-like behaviors in the SPT, TST, and FST. The effects of CP-101,606 were associated with a reversal of the CUMS-induced decrease in mTOR (Ser2448) and p70S6K (Thr389) phosphorylation and increasing PSD95 and GluA1 synthesis in the hippocampus.
Our results demonstrate that CP-101,606 produces antidepressant effects in CUMS mice, which may be mediated by mTOR signaling cascade upregulation. Our findings suggest the possible utility of CP-101,606 as a treatment for depression.
作为一种非竞争性N-甲基-D-天冬氨酸受体拮抗剂，氯胺酮对抑郁症具有起效快且持久的抗抑郁作用，但一些副作用限制了其应用。为了确定一种可能具有类似抗抑郁作用的更安全化合物，我们在此研究了选择性NR2B受体抑制剂CP-101,606是否具有类似的抗抑郁作用，并探讨其潜在机制。
为模拟抑郁样行为，将小鼠进行21天的慢性不可预测温和应激（CUMS）。分别用10、20和40mg/kg剂量的CP-101,606对小鼠进行7、14和21天的治疗，随后进行蔗糖偏好试验（SPT）、悬尾试验（TST）和强迫游泳试验（FST）。使用海马组织对多个靶点（mTOR、p-mTOR、p70S6K、p-p70S6K、PSD-95和GluA1）进行蛋白质印迹分析，同时进行免疫组织化学（GluA1）和免疫荧光（p-mTOR）检测。
20和40mg/kg剂量的CP-101,606治疗7天和14天，以及10mg/kg氟西汀和20mg/kg CP-101606治疗21天，均改善了SPT、TST和FST中的抑郁样行为。CP-101,606的作用与CUMS诱导的海马中mTOR（Ser2448）和p70S6K（Thr389）磷酸化降低的逆转以及PSD95和GluA1合成增加有关。
我们的结果表明，CP-101,606在CUMS小鼠中产生抗抑郁作用，这可能由mTOR信号级联上调介导。我们的发现提示CP-101,606作为抑郁症治疗药物的潜在效用。
