Mechanism of action of Panax ginseng alcohol extract based on orexin-mediated autophagy in the treatment of sleep and cognition in aged sleep-deprived rats

• Published in: Journal of ethnopharmacology 2025-01, Vol.337 (Pt 2), p.118907, Article 118907
• Main Authors: Lin, Haining, Xu, Yunlong, Xiong, Huazhong, Wang, Lichao, Shi, Yuqing, Wang, Dongyi, Wang, Zixu, Ren, Jixiang, Wang, Siming
• Format: Article
• Language: English
• Subjects: Aging - drug effects; alcohols; animal models; Animals; autophagosomes; Autophagy; Autophagy - drug effects; blood serum; Cognition; Cognition - drug effects; dietary supplements; enzyme-linked immunosorbent assay; Ethanol; fluorescent antibody technique; Hippocampal neuron; Hippocampus - drug effects; Hippocampus - metabolism; histopathology; Hypothalamus - drug effects; Hypothalamus - metabolism; immunohistochemistry; Male; mechanism of action; neurons; Orexin; Orexins - metabolism; Panax - chemistry; Panax ginseng; pentobarbital; phosphatidylinositol 3-kinase; Plant Extracts - pharmacology; rapamycin; Rats; Rats, Sprague-Dawley; secretion; Signal Transduction - drug effects; Sleep; Sleep - drug effects; sleep deprivation; Sleep Deprivation - drug therapy; therapeutics; traditional medicine; transmission electron microscopy; Western blotting
• ISSN: 0378-8741; 1872-7573; 1872-7573
• DOI: 10.1016/j.jep.2024.118907

Panax ginseng (P. ginseng) C. A. Meyer. has been used extensively globally as a medicine. It has a therapeutic effect on sleep and is an attractive alternative for patients with insomnia. The United States Patent of Invention has approved the use of P. ginseng alcohol extract (GAE) in nutraceuticals or food to improve sleep. It has shown promise as an effective therapeutic agent for improving sleep and cognition. However, its mechanism of action is not yet fully understood. To investigate the therapeutic benefits of GAE on sleep and cognition and its underlying mechanism in aged sleep-deprived rats, with a focus on orexin-mediated autophagy function. We conducted in vivo tests in an aged sleep-deprivation rat model produced using p-chlorophenylalanine (PCPA) coupled with modified multi-platform method to examine the therapeutic effects and mechanisms of GAE. A pentobarbital sodium-induced sleep test and water maze were used to assess sleep and cognitive performance, respectively. An enzyme-linked immunosorbent assay was used to determine orexin levels and aging and sleep markers in serum and hypothalamic tissues. Hematoxylin-eosin staining and Nissl staining were used to assess histopathological changes, and autophagy levels were assessed using transmission electron microscopy, immunofluorescence. Western blot and immunohistochemical staining were performed to detect the levels of orexin, orexin-receptor proteins, and autophagy-associated proteins to study the effects of GAE on hippocampal neurons, and the underlying mechanisms. In aged sleep-deprived rats, GAE treatment prolonged sleep duration, improved cognitive function, prevented hippocampal neuronal damage, increased the number of Nissl bodies, improved aging and sleep markers, and enhanced the LC3A/B expression in autophagosomes and neurons. The amount of orexin in serum and hypothalamic tissue and OX1R, OX2R, and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) proteins also reduced, which resulted in the inhibition of the PI3K/Akt/mTOR pathway and activation of the autophagy process. GAE may reduce hypothalamic orexin secretion and interact with orexin receptors to inhibit the PI3K/Akt/mTOR signalling network and activate autophagy. This may be a potential mechanism of action of GAE in regulating sleep-related cognitive function. [Display omitted] •GAE improved sleep duration and cognitive function in aged sleep-deprived rats.•GAE in aged sleep-depri