Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most robust neurobiological findings in the pathophysiology of major depressive disorder (MDD) over the last 40 years. The persistent increase in glucocorticoids levels induces morphological and anatomical changes in the brain, especially in the hippocampus. Ketamine represents a major advance for the treatment of MDD, however the psychotomimetic effects of this compound limit its widespread use. Agmatine is a neuromodulator that has been shown to be a putative novel and well-tolerated antidepressant/augmenter drug. In this study, the exposure of HT22 hippocampal neuronal cell line to corticosterone (50 μM) induced a significant neuronal cell death. Interestingly, the incubation of HT22 cells with the fast-acting antidepressant drug ketamine (1 μM) prevented the corticosterone-induced toxicity. Similarly, agmatine caused a significant cytoprotection at the concentration of 0.1 μM against corticosterone (50 μM) cell damage. Notably, the incubation with a subthreshold concentration of ketamine (0.01 μM) in combination with a subthreshold concentration of agmatine (0.001 μM) prevented the neuronal damage elicited by corticosterone (50 μM). A 24 h co-incubation with subthreshold concentrations of ketamine (0.01 μM) and agmatine (0.001 μM) was able to cause a significant increase in the phosphorylation levels of Akt (Ser⁴⁷³) and p70S6 kinase (Thr³⁸⁹) as well as PSD95 immunocontent. Neither glycogen synthase kinase-3β (Ser⁹) phosphorylation nor β catenin immunocontent were altered by a 24 h co-incubation period. Finally, the co-incubation of cells for 30 min did not produce any effect in the phosphorylation or immunocontent of any protein investigated. Taken together, our results support the notion that the combination of subthreshold concentrations of ketamine and agmatine has cytoprotective effects against corticosterone-induced cell death. This effect is accompanied by its ability to activate Akt and mTOR/S6 kinase signaling pathway, and increase the expression of synaptic proteins.

下丘脑-垂体-肾上腺（HPA）轴失调是过去40年中主要抑郁症（MDD）病理生理学中最可靠的神经生物学发现之一。糖皮质激素水平的持续增加会诱发大脑，尤其是海马体的形态和解剖变化。氯胺酮代表了治疗MDD的重大进展，但是该化合物的拟精神病作用限制了其广泛使用。胍丁胺是一种神经调节剂，已被证明是一种公认​​的新颖且耐受性良好的抗抑郁/增强药。在这项研究中，HT22海马神经元细胞系暴露于皮质酮（50μM）会引起明显的神经元细胞死亡。有趣的是，HT22细胞与速效抗抑郁药氯胺酮（1μM）的孵育可防止皮质酮诱导的毒性。类似地，胍丁胺在浓度为0.1μM的皮质酮（50μM）时可引起明显的细胞保护作用，从而防止细胞损伤。值得注意的是，亚阈值浓度的氯胺酮（0.01μM）与亚阈值浓度的胍丁胺（0.001μM）一起孵育可防止皮质酮（50μM）引起的神经元损伤。亚阈浓度浓度的氯胺酮（0.01μM）和胍丁胺（0.001μM）共孵育24小时能够导致Akt（Ser 亚阈值浓度的氯胺酮（0.01μM）与亚阈值浓度的胍丁胺（0.001μM）一起孵育可防止皮质酮（50μM）引起的神经元损伤。亚阈浓度浓度的氯胺酮（0.01μM）和胍丁胺（0.001μM）共孵育24小时能够导致Akt（Ser 亚阈值浓度的氯胺酮（0.01μM）与亚阈值浓度的胍丁胺（0.001μM）一起孵育可防止皮质酮（50μM）引起的神经元损伤。亚阈浓度浓度的氯胺酮（0.01μM）和胍丁胺（0.001μM）共孵育24小时能够导致Akt（Ser⁴⁷³）和p70S6激酶（Thr ³⁸⁹）以及PSD95免疫含量。共同孵育24小时后，糖原合酶激酶3β（Ser ⁹）的磷酸化和βcatenin的免疫含量均未改变。最后，将细胞共孵育30分钟不会对所研究的任何蛋白质的磷酸化或免疫含量产生任何影响。两者合计，我们的结果支持以下观点：亚阈浓度的氯胺酮和胍丁胺的组合具有对抗皮质酮诱导的细胞死亡的细胞保护作用。这种作用伴随着其激活Akt和mTOR / S6激酶信号传导途径并增加突触蛋白表达的能力。