20(S)-Protopanaxadiol (PPD) is one of the bioactive ingredients in ginseng and possesses neuroprotective properties. Brain-type creatine kinase (CK-BB) is an enzyme involved in brain energy homeostasis via the phosphocreatine–creatine kinase system. We previously identified PPD as directly bound to CK-BB and activated its activity in vitro. In this study, we explored the antidepressive effects of PPD that target CK-BB. First, we conducted time course studies on brain CK-BB, behaviors, and hippocampal structural plasticity responses to corticosterone (CORT) administration. Five weeks of CORT injection reduced CK-BB activity and protein levels and induced depression-like behaviors and hippocampal structural plasticity impairment. Next, a CK inhibitor and an adeno-associated virus-targeting CKB were used to diminish CK-BB activity or its expression in the brain. The loss of CK-BB in the brain led to depressive behaviors and morphological damage to spines in the hippocampus. Then, a polyclonal antibody against PPD was used to determine the distribution of PPD in the brain tissues. PPD was detected in the hippocampus and cortex and observed in astrocytes, neurons, and vascular endotheliocytes. Finally, different PPD doses were used in the chronic CORT-induced depression model. Treatment with a high dose of PPD significantly increased the activity and expression of CK-BB after long-term CORT injection. In addition, PPD alleviated the damage to depressive-like behaviors and structural plasticity induced by repeated CORT injection. Overall, our study revealed the critical role of CK-BB in mediating structural plasticity in CORT-induced depression and identified CK-BB as a therapeutic target for PPD, allowing us to treat stress-related mood disorders.

中文翻译：

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20(S)-原人参二醇作为脑型肌酸激酶的激活剂在慢性皮质酮诱导的啮齿动物模型中发挥抗抑郁作用

20( S )-原人参二醇 (PPD) 是人参中的生物活性成分之一，具有神经保护特性。脑型肌酸激酶 (CK-BB) 是一种通过磷酸肌酸-肌酸激酶系统参与脑能量稳态的酶。我们之前鉴定出 PPD 直接与 CK-BB 结合并在体外激活其活性。在这项研究中，我们探讨了针对 CK-BB 的 PPD 的抗抑郁作用。首先，我们对大脑 CK-BB、行为和海马结构可塑性对皮质酮 (CORT) 给药的反应进行了时间过程研究。五周的 CORT 注射降低了 CK-BB 活性和蛋白质水平，并诱发抑郁样行为和海马结构可塑性损伤。接下来，使用 CK 抑制剂和腺相关病毒靶向CKB来减少 CK-BB 活性或其在大脑中的表达。大脑中 CK-BB 的缺失会导致抑郁行为和海马体棘的形态损伤。然后，使用抗 PPD 多克隆抗体测定 PPD 在脑组织中的分布。 PPD 在海马和皮质中检测到，并在星形胶质细胞、神经元和血管内皮细胞中观察到。最后，在慢性CORT诱导的抑郁模型中使用不同的PPD剂量。长期注射CORT后，高剂量PPD治疗显着增加CK-BB的活性和表达。此外，PPD 还减轻了重复 CORT 注射引起的抑郁样行为和结构可塑性的损害。总体而言，我们的研究揭示了 CK-BB 在介导 CORT 诱导的抑郁症结构可塑性中的关键作用，并将 CK-BB 确定为 PPD 的治疗靶点，使我们能够治疗与压力相关的情绪障碍。