Neuroprotective Effects of Apocynin Derivatives in Epilepsy: Targeting NADPH Oxidase 4-mediated Neuronal Ferroptosis
Abstract number :
3.061
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2024
Submission ID :
487
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Lulu Yu, MB – Beijing Tiantan Hospital , Capital Medical University
Junmin Chen, MD – Beijing Tiantan Hospital , Capital Medical University
Anchen Guo, MD,PhD – Beijing Tiantan Hospital , Capital Medical University
Jianping Wu, MD,PhD – Beijing Tiantan Hospital , Capital Medical University
Qun Wang, MD – Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China
Rationale: Epilepsy is a common chronic neurological disorder, and existing antiepileptic seizure medications (ASMs) are mainly antiepileptic and do not prevent epilepsy onset or progression. Therefore, finding new therapeutic targets and drugs with mechanism of action to prevent or delay the epileptic process is an important goal of epilepsy modification therapy. The aim of this study was to elucidate whether Apocynin derivatives exert neuroprotective epileptic disease modification therapy (DMT) effects on epilepsy by inhibiting NADPH oxidase 4-mediated neuronal ferroptosis.
Methods: We pre-searched for compounds with 90% structural similarity of Apocynin, and screened and optimized the chemical structures by evaluating the blood-brain barrier permeability and antioxidant activity, and screened the compounds with high stability and strongest activity for the intervention study through in vivo and vitro experiments. In this study, primary cortical neurons were treated with Mg2+-free solution and pretreated with Apocynin derivative, Apocynin and Fer-1, an ferroptosis inhibitor, respectively, for 24 h. Western blot detected the protein levels of NOX4 and GPX4; ROS was detected by DCFH-DA fluorescent probe; colorimetric assay was used to detect GSH , MDA, and iron levels.
Results: Apocynin derivative pretreatment could reduce ROS production by inhibiting NOX4 in epileptic neurons, which in turn alleviated neuronal ferroptosis.
Conclusions: Apocynin derivatives exert neuroprotective effects on epilepsy by inhibiting NOX4-mediated neuronal ferroptosis, which is more advantageous than Apocynin and Fer-1.
Funding: National Key Research and Development Program of China (2022YFC2503800);National Natural Science Foundation of China(8237050142);Natural Science Foundation of Beijing (7232045);Capital Health Development and Research Project (2024-1-2041).
Basic Mechanisms