Ginsenoside Re attenuates Bay k-8644-induced self-injurious behaviors by enhancing Nrf2 and glutathione pathway in mice.

The pathophysiology of non-suicidal self-injury (NSSI) remains largely unknown; however, a few studies suggest that oxidative stress contributes to self-injurious behaviors associated with NSSI and other mental disorders. Bay k-8644, an activator of L-type voltage-gated calcium channels, has been reported to induce self-injurious behaviors, particularly in early adolescent mice, yet the role of oxidative stress remains elusive. Ginsenoside Re (GRe) exerts neuroprotective effects through various mechanisms, including antioxidant activity. In the present study, we investigated changes in the endogenous antioxidant system in this model and evaluated the effects of GRe. Bay k-8644 (50 μg, i.c.v.)-induced self-injurious behaviors were accompanied by decreased glutathione peroxidase (GPx) activity and GPx-1 expression in the striatum of mice, along with increased phosphorylation of protein kinase Cδ (PKCδ), one of the redox-sensitive kinases. These changes were associated with decreased Nrf2 activity and reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, suggesting that disruption of the GSH-related endogenous antioxidant system is involved in Bay k-8644-induced self-injurious behaviors. Pretreatment with GRe (20 mg/kg/day, p,o.) attenuated Bay k-8644-induced PKCδ phosphorylation, restored Nrf2 activity and the GSH/GSSG ratio, and prevented decreases in GPx activity and GPx-1 expression, thereby alleviating self-injurious behaviors in wild-type (WT) mice. Similarly, PKCδ gene knockout (KO) significantly inhibited these Bay k-8644-induced alterations. In contrast, GRe did not provide additional protective effects in PKCδ KO mice. These findings suggest that GRe attenuates Bay k-8644-induced self-injurious behaviors by restoring Nrf2 activity and GSH-related endogenous antioxidant system, in association with modulation of PKCδ signaling.