Liang Jinyuan, Zhang Jingxi, Sun Jingyu, Liang Qingsheng, Zhan Yingtong, Yang Zhiyou, Zhang Yongping, Jin Leigang, Hu Chuanyin, Zhao Yun-Tao
Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Modern Biochemistry Experimental Center, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health Guangdong Ocean University, Zhanjiang, China.
State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Food Funct. 2025 May 6;16(9):3408-3422. doi: 10.1039/d5fo00226e.
The ketogenic diet (KD) has been proposed as a potential treatment for depression. However, the underlying mechanisms remain poorly understood. This study aimed to evaluate further the effects of KD on chronic unpredictable mild stress (CUMS)-induced depression in mice and investigate the underlying mechanisms. The results demonstrated that KD intervention significantly alleviated CUMS-induced depression-like behaviors, as evidenced by a decrease in immobility time in the forced swimming test and tail suspension test, an increase in distance traveled in the open field test, and a greater preference for sucrose in the sucrose preference test. KD alleviated neuroinflammation by reducing the levels of glial cell activation markers Iba-1 and GFAP, inhibiting the expression of inflammatory factors IL-1β, TNF-α, and COX-2, and suppressing the overactivation of the TLR4/MyD88/NF-κB signaling pathway. Furthermore, KD increased the number of DCX-, BrdU-, and PSD95-positive cells in the hippocampus and enhanced the BDNF/TrkB/CREB and Wnt/β-catenin signaling pathways, thereby promoting hippocampal neurogenesis. These findings suggested that KD alleviated CUMS-induced depression-like behaviors in mice by reducing neuroinflammation, enhancing neurotrophic signaling, and promoting hippocampal neurogenesis, thereby providing a mechanistic basis for its potential as a novel dietary antidepressant therapy.
生酮饮食（KD）已被提议作为抑郁症的一种潜在治疗方法。然而，其潜在机制仍知之甚少。本研究旨在进一步评估KD对慢性不可预测轻度应激（CUMS）诱导的小鼠抑郁的影响，并探究其潜在机制。结果表明，KD干预显著减轻了CUMS诱导的抑郁样行为，这在强迫游泳试验和悬尾试验中不动时间的减少、旷场试验中行进距离的增加以及蔗糖偏好试验中对蔗糖的更大偏好中得到了证明。KD通过降低胶质细胞活化标志物Iba-1和GFAP的水平、抑制炎症因子IL-1β、TNF-α和COX-2的表达以及抑制TLR4/MyD88/NF-κB信号通路的过度激活来减轻神经炎症。此外，KD增加了海马中DCX、BrdU和PSD95阳性细胞的数量，并增强了BDNF/TrkB/CREB和Wnt/β-连环蛋白信号通路，从而促进海马神经发生。这些发现表明，KD通过减轻神经炎症、增强神经营养信号和促进海马神经发生来减轻CUMS诱导的小鼠抑郁样行为，从而为其作为一种新型饮食抗抑郁疗法的潜力提供了机制基础。
