Novel Antidepressant Mechanism of Ginsenoside Rg1 in Regulating the Dysfunction of the Glutamatergic System in Astrocytes

Abstract

Ginsenoside Rg1, a traditional Chinese medicine monomer, has been shown to have antidepressant effects. We previously found that Rg1 exerts antidepressant effects by improving the gap junction channels (GJCs) dysfunction; however, the downstream mechanisms through which Rg1 ameliorates GJC dysfunction remain unclear. Since hemichannels directly release glutamate, GJC dysfunction decreases the expression levels of glutamate transporters in astrocytes, and glutamatergic system dysfunction plays an essential role in the pathogenesis of depression. The glutamatergic system may be a potential downstream target of Rg1 that exerts antidepressant effects. Therefore, in this study, we aimed to determine the downstream mechanisms by which Rg1 ameliorated GJC dysfunction and exerted its antidepressant effects. Corticosterone (CORT) is used to mimic high glucocorticoid levels in patients with depression in vitro. Primary cortical astrocytes were isolated and phosphorylation of connexin43 (Cx43) as well as the functions of hemichannels, GJCs, and the glutamatergic system were evaluated after drug treatment. Rg1 pretreatment reversed the anomalous activation of Cx43 phosphorylation as well as the dysfunction of hemichannels, GJCs, and the glutamatergic system induced by CORT. These results suggest that Rg1 can ameliorate CORT-induced dysfunction of the glutamatergic system in astrocytes by potentially reducing Cx43 phosphorylation and inhibiting opening of hemichannels, thereby improving GJC dysfunction.

Connexin 43 Phosphorylation: Implications in Multiple Diseases

“…By reducing the malfunctioning of gap junction channels (GJCs), Rg1 has antidepressant effects. It is possible that the improved function of GJCs may be due to Rg1 reversing the increased phosphorylation of Cx43 at Tyr265 and Ser279 sites induced by CORT [ 35 ]. Chronic unpredictable stress can increase C-Src expression.…”