7,8‑Dihydroxyflavone functions as an antioxidant through the inhibition of Kelch‑like ECH‑associated protein 1: Molecular docking and an in vivo approach in a rat model of ischemia‑reperfusion brain injury

Abstract

Stroke is a medical condition characterized by a sudden, localized neurological impairment caused by damage to the central nervous system due to either a blockage or bleeding in the blood vessels. This process leads to increased oxidation, which can exacerbate brain damage. Flavonoids are compounds that are widely found in nature and are considered to have numerous health benefits. 7,8-dihydroxyflavone (7,8-DHF) is a flavonoid that has tropomyosin receptor kinase B agonist activity. However, the other beneficial activities of 7,8-DHF remain to be explored, particularly in neuron-related diseases. The present study aimed to explore 7,8-DHF as an antioxidant agent using in vivo and in silico analyses. An in vivo experiment was conducted using Rattus novergicus, in which ischemia-reperfusion brain injury was induced. A total of 30 rats were divided into the sham-operated, control and treatment groups. The treatment groups were administered doses of 10, 20 and 50 mg/kg body weight of 7,8-DHF orally, once daily for a duration of 14 days following the induction of ischemia-reperfusion brain injury. Subsequently, blood and brain tissues were collected for the examination of nuclear factor E2-related factor 2 (Nrf2) expression, glutathione peroxidase-1 (GPX-1) expression and the malondialdehyde (MDA) level. Molecular docking analysis and dynamic simulations of 7,8-DHF and Kelch like ECH-associated protein 1 (Keap1) protein interactions were performed using AutoDock Vina and AMBER. The visualization of the interaction was performed using ChimeraX and Discovery Studio. The drug-like properties of 7,8-DHF were predicted using the SwissADME web server, and the bioactivity of the compounds was evaluated using the PASS online server. The results revealed that 7,8-DHF exhibits antioxidant activity through the inhibition of Keap1, thereby increasing Nrf2 and GPX-1 expression and decreasing the levels of MDA. In silico analysis revealed that 7,8-DHF can bind Keap1 protein, thereby disrupting the interaction between Nrf2 and Keap1. Molecular dynamics also demonstrated that 7,8-DHF has good stability compared to the control. On the whole, as demonstrated in the present study