Vortioxetine mitigates neuronal damage by restricting PERK/eIF2α/ATF4/CHOP signaling pathway in rats subjected to focal cerebral ischemia-reperfusion

Abstract

AimsStroke has risen to the fifth and third most common causes of death in the United States and the rest of the world, respectively. Vortioxetine (VTX) is a multimodal antidepressant agent that balances 5-HT receptors and represses the serotonin transporter. Our study aimed to examine the neuroprotective impacts of VTX against cerebral ischemia caused by occluding the middle cerebral artery (MCA). Main methodsUntil the middle cerebral artery occlusion (MCAO) induction, VTX (10 mg/kg/day) was taken orally for 14 days. Behavioral assessments were carried out 24 h after the MCAO technique. The hippocampal and cortical tissues of the brain were isolated to assess the histological changes and the levels of the biochemical parameters. Key findingsMCAO damage led to severe neurological deficits and histopathological damage. However, VTX improved MCAO-induced neurological deficits and ameliorated histopathological changes in both hippocampal and cortical tissues of MCAO rats. Western blot analysis showed increments of p-PERK, CHOP, ASK-1, NICD, HES-1, HES-5, and p-eIF2α expression levels in MCAO rats. Moreover, ELISA revealed an increase in the levels of ATF4, IRE1, Apaf-1, and HIF-1α, while VTX administration ameliorated most of these perturbations induced after MCAO injury. SignificanceThis research suggests that VTX could be a potent neuroprotective agent against ischemic stroke by inhibiting a variety of oxidative, apoptotic, inflammatory, and endoplasmic reticulum stress pathways.