Sun Bo, Jia Xiayan, Yang Fei, Ren Guoyong, Wu Xuemei
Department of Neurology, General Hospital of TISCO, Taiyuan, China.
Department of Neurology, The Second Hospital of Shanxi Medical University, Taiyuan, China.
Neurosci Res. 2021 Apr;165:38-44. doi: 10.1016/j.neures.2020.05.003. Epub 2020 May 16.
Metabolic disorder particularly diabetes is one of the leading causes of psychiatric or other neurodegenerative diseases. Previous clinical and pre-clinical studies indicate anti-diabetic drugs such as GLP-1 analogs or GLP-1 receptor (GLP-1R) agonists could perform the neuroprotective effects with multiple molecular mechanisms. As one of natural compound to stimulate GLP-1R, geniposide was reported could improve cognitive behaviors in diabetes associated Alzheimer's disease rat model. Stimulating of GLP-1R could act the crosstalk downstream like neurotrophic factor mediated cAMP-response element binding protein (CREB) would be activated and exert cellular events including promotion of adult neurogenesis, which is one of important treatment targets in antidepressant. Here in this study, we employed HDF in combined with corticosterone (CORT) treatment to create diabetes associated depression model. Geniposide treatment could not only correct the metabolic pattern but could also improve the cognitive dysfunctions and depressive/anxiety symptoms. In consistent with its pro-neurogenic effects, geniposide also enhanced the activity of CREB in hippocampal tissue. Moreover, blocking CREB activity with 666-15 significantly compromised the effects of geniposide in promotion of neurogenesis and behavioral protective effects. In conclusion, this study expands the application of geniposide to treat diabetes associated depression subject and identified the underlying molecular mechanism for such effects.
代谢紊乱尤其是糖尿病是精神疾病或其他神经退行性疾病的主要病因之一。先前的临床和临床前研究表明，抗糖尿病药物如胰高血糖素样肽-1（GLP-1）类似物或GLP-1受体（GLP-1R）激动剂可通过多种分子机制发挥神经保护作用。作为一种刺激GLP-1R的天然化合物，据报道栀子苷可改善糖尿病相关阿尔茨海默病大鼠模型的认知行为。刺激GLP-1R可在下游发挥相互作用，如神经营养因子介导的环磷酸腺苷反应元件结合蛋白（CREB）会被激活，并引发包括促进成体神经发生在内的细胞事件，而成体神经发生是抗抑郁治疗的重要靶点之一。在本研究中，我们采用人皮肤成纤维细胞（HDF）联合皮质酮（CORT）处理来建立糖尿病相关抑郁症模型。栀子苷治疗不仅可以纠正代谢模式，还可以改善认知功能障碍以及抑郁/焦虑症状。与其促神经发生作用一致，栀子苷还增强了海马组织中CREB的活性。此外，用666-15阻断CREB活性显著削弱了栀子苷在促进神经发生和行为保护方面的作用。总之，本研究拓展了栀子苷在治疗糖尿病相关抑郁症方面的应用，并确定了其作用的潜在分子机制。
