Novel antidepressant mechanism of ginsenoside Rg1: Regulating biosynthesis and degradation of connexin43

Ethnopharmacological relevance: Panax ginseng C. A. Meyer is a valuable medicinal herb and alternative remedy for the prevention and treatment of depression. Dysfunction of connexin43 (Cx43)-gap junction in astrocytes is predisposed to the precipitation of depression. Ginsenoside Rg1 (Rg1), the main bioactive constituent extracted from ginseng, is efficacious in the management of depression by upregulating the content of Cx43. Our previous results indicated that pretreatment with Rg1 significantly improved Cx43-gap junction in corticosterone (CORT)treated astrocytes. However, the antidepressant mechanism underlying how Rg1 upregulates Cx43-gap junction in astrocytes hasn't been proposed. Aim of the study: To dissect the mechanisms of Rg1 controlling Cx43 levels in primary astrocytes. Methods: We examined the changes of the level of Cx43 mRNA, the degradation of Cx43, as well as the ubiquitinproteasomal and autophagy-lysosomal degradation pathways of Cx43 followed by Rg1 prior to CORT in rat primary astrocytes isolated from prefrontal cortex and hippocampus. Furthermore, the recognized method of scrape loading/dye transfer was performed to detect Cx43-gap junctional function, an essencial indicator of the antidepressant effect. Results: Pretreatment with Rg1 could reverse CORT-induced downregulation of Cx43 biosynthesis, acceleration of Cx43 degradation, and upregulation of two Cx43 degradation pathways in primary astrocytes. Conclusion: The findings in the present study provide the first evidence highlighting that Rg1 increases Cx43 protein levels through the upregulation of Cx43 mRNA and downregulation of Cx43 degradation, which may be attributed to the effect of Rg1 on the ubiquitin-proteasomal and autophagy-lysosomal degradation pathways of Cx43.

Automated summary

Panax ginseng is a valuable herb for the prevention and treatment of depression, with its main bioactive constituent, ginsenoside Rg1, upregulating the level of Cx43 in astrocytes. The study aims to dissect the mechanisms of Rg1 controlling Cx43 levels in primary astrocytes, showing that Rg1 can reverse CORT-induced downregulation of Cx43 biosynthesis and acceleration of Cx43 degradation. The findings suggest that Rg1 increases Cx43 protein levels through the upregulation of Cx43 mRNA and downregulation of Cx43 degradation pathways.