Research reportAntidepressant-like effects of Cortex Mori Radicis extract via bidirectional phosphorylation of glucocorticoid receptors in the hippocampus

Excessive and prolonged secretion of adrenal glucocorticoids leads to a wide range of pathophysiological processes, including depression. Glucocorticoids, which act at glucocorticoid receptors (GR), are key regulators of the limbic hypothalamic-pituitary-adrenocortical (HPA) axis. In the present study, the antidepressant-like effects of the alcohol extract Cortex Mori Radicis (CMR) and its role in GR signalling were investigated. Male Wistar rats were administered CMR extract (50, 100, 200 mg/kg, p.o.) daily for 5 days and then exposed to the forced swim test (FST). Behavioural analyses showed that CMR extract dose-dependently decreased immobility time during forced swimming. CMR extract also decreased the limbic HPA axis response to the FST, as indicated by an attenuated corticosterone response and decreased c-fos immunoreactivity in the dentate gyrus. Reduced hippocampal GR expression following exposure to the FST was reversed by CMR treatment. Moreover, a prominent increase in GR phosphorylation at S232 and a decrease at S246 were noted following treatment with CMR. This resulted in a high pGR(S232)/(S246) ratio. CMR treatment also produced a downregulation of serine/threonine protein phosphatase 5 levels, producing a strong negative relationship with pGR(S232). Taken together, our findings suggest that the alcohol extract CMR promotes antidepressant-like effects through bidirectional phosphorylation of GR at S232 and S246.

► CMR extract treatment dose-dependently produced antidepressant-like effect. ► CMR extract treatment ameliorated stress-induced dysregulation of the HPA axis. ► We demonstrated a bifunctional activity of CMR extract on GR phosphorylation. ► The bifunctional effect was significantly associated with the level of PP5 protein.