Vortioxetine modulates Nrf2/HO-1 signaling and antioxidant defense in a cuprizone-induced demyelination model

Abstract

Aim: To evaluate the effects of vortioxetine on oxidative stress and antioxidant defense responses through the regulation of the Nrf2/HO-1 signaling pathway in a mouse model of cuprizone-induced demyelination, representing experimental Multiple Sclerosis (MS).

Method: Twenty-four male C57Bl/6 mice were randomly divided into four groups: control, cuprizone, cuprizone + vortioxetine, and vortioxetine. Demyelination was induced by administering cuprizone (10 mg/kg) via oral gavage every alternate day for a duration of 5 weeks. Vortioxetine (10 mg/kg) was delivered intraperitoneally to the appropriate groups for the same period. Biochemical analyses were conducted to assess nuclear and total Nrf2, HO-1, and total antioxidant status (TAS).

Results: Cuprizone treatment led to a significant increase in HO-1 levels compared to the control group while co-administration with vortioxetine significantly reduced HO-1 levels relative to the cuprizone group. Nuclear Nrf2 expression was elevated in the cuprizone group and significantly decreased in the vortioxetine co-treatment group. The nuclear-to-total Nrf2 ratio was significantly lower in the co-treatment group compared to cuprizone group. TAS levels were significantly increased in both the cuprizone and cuprizone + vortioxetine groups relative to control, whereas TAS values in the vortioxetine group were significantly lower when compared to the co-treatment group and the cuprizone group.

Conclusions: Vortioxetine effectively modulated the Nrf2/HO-1 pathway and reduced oxidative stress in a mouse model of demyelination. These findings suggest the potential of vortioxetine as a therapeutic agent for demyelinating diseases, such as MS.