Glycyrrhizic acid treatment ameliorates anxiety-like behaviour via GLT1 and Per1/2-dependent pathways

• Published in: Journal of ethnopharmacology Vol. 328; p. 118013
• Main Authors: Ma, Shanbo, Chong, Ye, Zhang, Rui, Quan, Wei, Gui, Jiayue, Li, Long, Wang, Jin, Miao, Shan, Shi, Xiaopeng, Zhao, Minggao, Zhang, Kun
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.06.2024
• Subjects: Anxiety; Chronic restraint stress; Glutamate; Glycyrrhizic acid; Per1/2; Per1/2; Anxiety; Glycyrrhizic acid; Chronic restraint stress; Glutamate
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2024.118013

As a traditional Chinese medicinal herb, Glycyrrhiza. Fisch. (licorice root, chinese name: Gancao) has a variety of medicinal values and is widely used clinically. Its main active ingredient, glycyrrhizic acid (GA), is believed to have a neuroprotective effect. However, the underlying biological mechanisms of GA on stress-induced anxiety disorders are still unclear. To investigate the anti-anxiety effect of GA and its underlying mechanism. We selected the anxiety model induced by repeated chronic restraint stress (CRS) for 2 h on each of 7 consecutive days. GA (4, 20, 100 mg/kg) was injected intraperitoneally once daily for 1 week. The potential GA receptors were identified using whole-cell patches and computer-assisted docking of molecules. High-throughput RNA sequencing, adeno-associated virus-mediated gene regulation, Western blotting, and RT-qPCR were used to assess the underlying molecular pathways. GA alleviate depression-like and anxiety-like behaviors in CRS mice. GA decreased synaptic transmission by facilitating glutamate reuptaking in mPFC. Meanwhile, long-term GA treatment increased the expression of clock genes Per1 and Per2. Suppressing both Per1 and Per2 abolished the anxiolytic effects of GA treatment. Our study suggests that GA may be developed for the treatment of stress-induced anxiety disorders, and its mechanism is related to GLT1 and Per1/2-dependent pathways. This presents a novel approach to discovering potent therapeutic drugs. [Display omitted] •GA improves anxiety-like behaviour.•GA reduces neuronal excitability.•Glycyrrhizic acid facilitates glutamate re-uptake in a GLT1-dependent pathway.•GA regulates the expression of Per1 and Per2.•As a traditional Chinese medicinal her, glycyrrhiza has a variety of medicinal values and is widely used clinically. Its main active ingredient, glycyrrhizic acid (GA), is believed to have a neuroprotective effect. However，the underlying biological mechanisms of GA on stress-induced anxiety disorders are still unclear. This study detected the underlying mechanism of anxiolytic effects after short-term and long-term treatments with GA. The results showed that a single GA injection as well as chronic GA treatment elicited a significant anxiolytic effect in mice receiving chronic restraint stress. GA decreased synaptic transmission by facilitating the re-uptake in mPFC. Meanwhile, long-term GA treatment increased the expression of clock genes, Per1 and Per2. Suppressing both Per1 and Per2 reduced anxiolytic effects of long-term GA treatment, suggesting two different mechanisms mediating anxiolytic effects of GA. Our study suggests that GA may be developed to treat stress-induced anxiety disorders. This presents a novel approach towards discovering potent therapeutic drugs.