Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències (UBneuro), University of Barcelona, 08036 Barcelona, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
Mar Drugs. 2022 Oct 19;20(10):648. doi: 10.3390/md20100648.
Major depression disorder (MDD) is a severe mental alteration with a multifactorial origin, and chronic stress is one of the most relevant environmental risk factors associated with MDD. Although there exist some therapeutical options, 30% of patients are still resistant to any type of treatment. GSK3β inhibitors are considered very promising therapeutic tools to counteract stress-related affectations. However, they are often associated with excessive off-target effects and undesired secondary alterations. Meridianins are alkaloids with an indole framework linked to an aminopyrimidine ring from Antarctic marine ascidians. Meridianins could overcome several of the aforementioned limitations since we previously demonstrated that they can inhibit GSK3β activity without the associated neurotoxic or off-target effects in rodents. Here, we show that meridianins delivered into the lateral ventricle inhibited GSK3β in several brain regions involved with stress-related symptoms. We also observed changes in major signaling pathways in the prefrontal cortex (Akt and PKA) and hippocampus (PKC and GluR1). Moreover, meridianins increased synaptic activity, specifically in the CA1 but not in the CA3 or other hippocampal subfields. Finally, we chronically treated the mice subjected to an unpredictable mild chronic stress (CUMS) paradigm with meridianins. Our results showed improvements produced by meridianins in behavioral alterations provoked by CUMS. In conclusion, meridianins could be of therapeutic interest to patients with stress-related disorders such as MDD.
重度抑郁症（MDD）是一种严重的精神障碍，具有多因素起源，慢性应激是与 MDD 相关的最重要的环境风险因素之一。尽管存在一些治疗选择，但仍有 30%的患者对任何类型的治疗都没有反应。GSK3β 抑制剂被认为是对抗与应激相关的影响的非常有前途的治疗工具。然而，它们通常与过度的脱靶效应和不期望的次要改变相关。麦角灵是一种具有吲哚骨架的生物碱，与来自南极海洋海鞘的氨基嘧啶环相连。麦角灵可以克服上述许多限制，因为我们之前证明它们可以抑制 GSK3β 活性，而不会在啮齿动物中引起神经毒性或脱靶效应。在这里，我们表明，侧脑室给药的麦角灵可以抑制与应激相关症状相关的几个脑区中的 GSK3β。我们还观察到前额叶皮层（Akt 和 PKA）和海马（PKC 和 GluR1）中主要信号通路的变化。此外，麦角灵增加了突触活性，特别是在 CA1 区，但不在 CA3 区或其他海马亚区。最后，我们用麦角灵对接受不可预测的轻度慢性应激（CUMS）范式处理的小鼠进行了慢性治疗。我们的结果表明，麦角灵可以改善 CUMS 引起的行为改变。总之，麦角灵可能对与应激相关的疾病（如 MDD）患者具有治疗意义。
