Mesembryanthemum tortuosum L. alkaloids modify anxiety-like behaviour in a zebrafish model. (23rd May 2022)

• Record Type: Journal Article
• Authors: Maphanga, Veronica B.; Skalicka-Wozniak, Krystyna; Budzynska, Barbara; Skiba, Andriana; Chen, Weiyang; Agoni, Clement; Enslin, Gill M.; Viljoen, Alvaro M.
• Is Part Of: Journal of ethnopharmacology. Volume 290(2022)
• Publication Date: 2022-05-23
• Subjects: Mesembryanthemum tortuosum -- Sceletium alkaloids -- ADMET -- Zebrafish larvae -- Reverse-thigmotaxis; Ethnopharmacology -- Periodicals; Pharmacognosy -- Periodicals; Herbs -- Periodicals; Herbs -- Periodicals; Pharmacognosy -- Periodicals; Pharmacognosie -- Périodiques; Herbes -- Périodiques; 615.1
• DOI: 10.1016/j.jep.2022.115068
• Languages: English
• ISSNs: 0378-8741

Abstract

Abstract: Ethnopharmacological relevance: Mesembryanthemum tortuosum L. (previously known as Sceletium tortuosum (L.) N.E. Br.) is indigenous to South Africa and traditionally used to alleviate anxiety, stress and depression. Mesembrine and its alkaloid analogues such as mesembrenone, mesembrenol and mesembranol have been identified as the key compounds responsible for the reported effects on the central nervous system. Aim of the study: To investigate M. tortuosum alkaloids for possible anxiolytic-like effects in the 5-dpf in vivo zebrafish model by assessing thigmotaxis and locomotor activity. Materials and methods: Locomotor activity and reverse-thigmotaxis, recognised anxiety-related behaviours in 5-days post fertilization zebrafish larvae, were analysed under simulated stressful conditions of alternating light-dark challenges. Cheminformatics screening and molecular docking were also performed to rationalize the inhibitory activity of the alkaloids on the serotonin reuptake transporter, the accepted primary mechanism of action of selective serotonin reuptake inhibitors. Mesembrine has been reported to have inhibitory effects on serotonin reuptake, with consequential anti-depressant and anxiolytic effects. Results: All four alkaloids assessed decreased the anxiety-related behaviour of zebrafish larvae exposed to the light-dark challenge. Significant increases in the percentage of time spent in the central arena during the dark phase were also observed when larvae were exposed to the pure alkaloids (mesembrenone, mesembrenol, mesembrine and mesembrenol) compared to the control. However, mesembrenone and mesembranol demonstrated a greater anxiolytic-like effect than the other alkaloids. In addition to favourable pharmacokinetic and physicochemical properties revealed via in silico predictions, high-affinity interactions characterized the binding of the alkaloids with the serotonin transporter. Conclusions: M. tortuosum alkaloids demonstrated an anxiolytic-like effect in zebrafish larvae providing evidence for its traditional and modern day use as an anxiolytic. Graphical abstract: Image 1 Highlights: Four M. tortuosum alkaloids demonstrated moderation of anxiety-like behaviour in zebrafish larvae under simulated stressful conditions. In silico predictions revealed favourable pharmacokinetic and physicochemical properties for the four alkaloids and high-affinity interactions characterized the binding of the alkaloids with the serotonin transporter. The observed activity is indicative of a potential anxiolytic effects, providing supportive evidence for the traditional use of the plant as a treatment for depression and anxiety. With demonstrated in vivo efficacy in an animal model and in silico prediction of suitable drug-like properties, these four compounds may be promising leads for the development of new anti-depressant and anxiolytic medicines.