Keap1/Nrf2 signaling pathway participating in the progression of epilepsy via regulation of oxidative stress and ferroptosis in neurons

Highlights

• Role of the Keap1/Nrf2 pathway in epilepsy.

• Effects of the Keap1/Nrf2 pathway on ferroptosis and oxidative stress in neuronal cells.

• Effect of Keap1/Nrf2 pathway on neuronal cell activity in epileptic rats.

Abstract

Objective

This study aims to analyze the relationship between the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor-erythroid 2-related factor 2 (Nrf2) and Epilepsy (EP), as well as its mechanism of action.

Methods

Thirty Wistar rats were divided into a control group (without treatment), a model group (EP modeling), and an inhibition group (EP modeling + intervention by Keap1/Nrf2 signaling pathway inhibitor ATRA) and subject to Morris water maze experiment. Then, the expression of Oxidative Stress (OS) markers, ferroptosis-associated proteins and Keap1/Nrf2 pathway in rat hippocampus was measured. In addition, rat hippocampal neuronal cell HT22 was purchased and treated accordingly based on the results of grouping, and cell proliferation and apoptosis in the three groups were determined.

Results

Compared with rats in the model group, those in the inhibition group showed shorter escape latency and an increased number of platform crossings (p < 0.05). Significant OS and neuron ferroptosis, increased apoptosis rate, elevated Keap1 expression, and decreased Nrf2 expression were observed in the model group compared to the control group (p < 0.05). The inhibition group exhibited notably improved OS and ferroptosis, as well as enhanced neuronal viability (p < 0.05).

Conclusion

Inhibition of the Keap1/Nrf2 pathway can reverse the OS and neuron viability in EP rats.

Keywords
Keap1/Nrf2 signaling pathway; Oxidative stress; Ferroptosis; Epilepsy; Neuronal cell