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

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 γ-aminobutyric acid A receptor α1 (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.

Effect of rhynchophylline on the expression of p-CREB and sc-Fos in triatum and hippocampal CA1 area of methamphetamine-induced conditioned place preference rats.

To explore the effect of rhynchophylline (Rhy) on the expression of p-CREB and c-Fos in the striatum and hippocampal CA1 area of methamphetamine-induced conditioned place preference (CPP) rat, methamphetamine (2 mg/kg) was injected to rats and the conditioned place preference was observed in these rats treated with or without Rhy. An immunohistochemistry assay was used to determine the expression of p-CREB and c-Fos in the striatum and hippocampal CA1 area. Methamphetamine induced significant behavior alteration in CPP, while after pretreatment with rhynchophylline or ketamine, the time of staying in methamphetamine-paired compartment of rats was significantly reduced. Methamphetamine also increased the number of p-CREB positive cells in the striatum and hippocampal CA1 zone, as well as p-Fos positive cells. However, the compound Rhy could attenuate the effect. These findings show that Rhy can suppress the acquisition of CPP in rats induced by methamphetamine and the action may be related with the reduced expression of p-CREB and p-Fos in the striatum and hippocampus.

Hypoglycemic and Hypolipidemic Effects of Ethanolic Extract of Mirabilis jalapa L. Root on Normal and Diabetic Mice.

The present study investigated the insulin sensitivity, hypoglycemic, and hypolipidemic activities of ethanolic extract of Mirabilis jalapa L. root (EEM) in normal and diabetic mice. After induction of diabetes with streptozotocin, both normal and diabetic mice were singly or repeatedly for 28 days administrated with EEM at doses of 2, 4, 8 g/kg, respectively. Before induction of diabetes, mice were administrated with EEM at doses of 2, 4, 8 g/kg for 14 days and were injected with streptozotocin and continued on EEM administration for another 28 days. Both after and before induction of diabetes, repeated administration with 4, 8 g/kg EEM continually lowered blood glucose level, decreased serum insulin level and improved insulin sensitivity index, and lowered serum total cholesterol, triglyceride levels and triglyceride content in liver and skeletal muscle, and increased glycogen content in these tissues; but repeated administration had no influence on those indexes of normal mice. Single administration with EEM (4, 8 g/kg) showed hypoglycemic effect in oral glucose tolerance test in normal and diabetic mice. Single administration with EEM had no hypoglycemic and hypolipidemic effects on normal and diabetic mice. These results suggest that EEM possesses both potential insulin sensitivity, hypoglycemic, and hypolipidemic effects on diabetes.