State Key Laboratory of Reliability and Intelligence of Electrical Equipment, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, 300130 Tianjin, China; College of Life Sciences, Nankai University, 300071 Tianjin, China.
College of Life Sciences, Nankai University, 300071 Tianjin, China.
J Affect Disord. 2024 Nov 15;365:213-221. doi: 10.1016/j.jad.2024.08.088. Epub 2024 Aug 16.
The excessive secretion of glucocorticoids resulting from the overactivation of the hypothalamic-pituitary-adrenal axis is a crucial factor in the pathogenesis of depression. RIPK3 plays a significant role in apoptosis and necroptosis. Glucocorticoids have been implicated in directly regulating the expression of RIPK3, leading to apoptosis and necroptosis of osteoblasts. This suggests that RIPK3 may contribute to cell death induced by glucocorticoids. However, the precise involvement of RIPK3 in glucocorticoid-induced depression remains poorly understood.
In this study, a mouse model of depression was established by repeated corticosterone injections to examine the impact of RIPK3 knockdown on depression-like behavior. Additionally, a corticosterone-induced HT22 injury model was also established to investigate the role of RIPK3 in corticosterone-induced neuronal cell death and underlying mechanisms.
Our findings demonstrate that hippocampal RIPK3 knockdown effectively ameliorated depression-related symptoms and restored synaptic plasticity impairment caused by corticosterone. Furthermore, treatment with the RIPK3 inhibitor GSK872 in vitro successfully mitigated corticosterone-induced HT22 cell death. Additionally, the administration of a free radical scavenger alleviated neuronal death and effectively suppressed the expression of corticosterone-induced RIPK3.
The limitation of this study is that only the changes of RIPK3 in the hippocampus of depressed male animals were studied.
These results suggest that corticosterone may induce RIPK3-dependent neuronal cell death and impair synaptic plasticity through the generation of high levels of oxidative stress, ultimately leading to depression-like behavior.
下丘脑-垂体-肾上腺轴过度激活导致糖皮质激素分泌过多，是抑郁症发病机制的一个关键因素。RIPK3 在细胞凋亡和坏死性凋亡中发挥重要作用。糖皮质激素被认为可以直接调节 RIPK3 的表达，导致成骨细胞凋亡和坏死性凋亡。这表明 RIPK3 可能参与了糖皮质激素诱导的细胞死亡。然而，RIPK3 在糖皮质激素诱导的抑郁症中的具体作用仍知之甚少。
本研究通过重复给予皮质酮注射建立了抑郁小鼠模型，以观察 RIPK3 敲低对抑郁样行为的影响。此外，还建立了皮质酮诱导的 HT22 损伤模型，以研究 RIPK3 在皮质酮诱导的神经元细胞死亡中的作用及其潜在机制。
我们的研究结果表明，海马 RIPK3 敲低可有效改善皮质酮引起的抑郁相关症状，并恢复皮质酮引起的突触可塑性损伤。此外，体外使用 RIPK3 抑制剂 GSK872 可成功减轻皮质酮诱导的 HT22 细胞死亡。此外，自由基清除剂的给药可减轻神经元死亡，并有效抑制皮质酮诱导的 RIPK3 表达。
本研究的局限性在于仅研究了抑郁雄性动物海马中 RIPK3 的变化。
这些结果表明，皮质酮可能通过产生高水平的氧化应激诱导 RIPK3 依赖性神经元细胞死亡和损害突触可塑性，最终导致抑郁样行为。
