Rhynchophylline inhibits methamphetamine dependence via modulating the miR-181a-5p/GABRA1 axis

作者：Jiang, Ming-Jin; Li, Jing; Luo, Chao-Hua; Zhu, Chen; Chen, Zhi-Jie; Bai, Wei; Hu, Tian-Yu; Feng, Chuan-Hua; Li, Chan^*; Mo, Zhi-Xian^*

来源：Journal of Ethnopharmacology, 2023, 314: 116635.

DOI：10.1016/j.jep.2023.116635

• Rhynchophylline
• Methamphetamine dependence
• miR-181a-5p
• GABRA1
• Hippocampus
• PC12 cells

Ethnopharmacological relevance: Uncaria rhynchophylla (Miq.) Miq. ex Havil. is a plant species that is routinely devoted in traditional Chinese medicine to treat central nervous system disorders. Rhynchophylline (Rhy), a predominant alkaloid isolated from Uncaria rhynchophylla (Miq.) Miq. ex Havil., has been demonstrated to reverse methamphetamine-induced (METH-induced) conditioned place preference (CPP) effects in mice, rats and zebrafish. The precise mechanism is still poorly understood, thus further research is necessary. Aim of study: This study aimed to investigate the role of miRNAs in the inhibitory effect of Rhy on METH dependence. Materials and methods: A rat CPP paradigm and a PC12 cell addiction model were established. Microarray assays were used to screen and identify the candidate miRNA. Behavioral assessment, real-time PCR, dual-luciferase reporter assay, western blotting, stereotaxic injection of antagomir/agomir and cell transfection experiments were performed to elucidate the effect of the candidate miRNA and intervention mechanism of Rhy on METH dependence. Results: Rhy successfully reversed METH-induced CPP effect and the upregulated miR-181a-5p expression in METH-dependent rat hippocampus and PC12 cells. Moreover, suppression of miR-181a-5p by antagomir 181a reversed METH-induced CPP effect. Meanwhile, overexpression of miR-181a-5p by agomir 181a in combination with low-dose METH (0.5 mg/kg) elicited a significant CPP effect, which was blocked by Rhy through inhibiting miR-181a-5p. Finally, the result demonstrated that miR-181a-5p exerted its regulatory role by targeting gamma-aminobutyric acid A receptor alpha 1 (GABRA1) both in vivo and in vitro. Conclusion: This finding reveals that Rhy inhibits METH dependence via modulating the miR-181a-5p/GABRA1 axis, which may be a promising target for treatment of METH dependence.

• 单位
  南昌大学; 广州大学; 1; 南方医科大学