Sestrin 3 promotes oxidative stress primarily in neurons following epileptic seizures in rats

Rhoda Olowe Taiwo, Sereen Sandouka, Aseel Saadi, Stjepana Kovac, Tawfeeq Shekh-Ahmad*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Epilepsy affects approximately 1% of the global population, with 30% of patients experiencing uncontrolled seizures despite treatment. Reactive oxygen species (ROS) and oxidative stress have been implicated in the pathogenesis of epilepsy. Sestrins are stress-inducible proteins that regulate the ROS response. In particular, Sestrin 3 (SESN3) has been implicated in ROS accumulation and the regulation of proconvulsant genes. To investigate the role of SESN3 in epilepsy, we studied its involvement in rat models of acute seizures and temporal lobe epilepsy. Our results showed that downregulation of SESN3 reduced the oxidative stress induced by seizure activity in neuronal cultures. After acute seizure activity, SESN3 protein levels temporarily increased as early as 3 h after the seizure, whereas kainic acid-induced status epilepticus led to a significant and persistent increase in SESN3 protein levels in the cortex and hippocampus for up to 2 weeks post-status epilepticus. In the chronic epilepsy phase, when spontaneous seizures emerge, SESN3 protein expression is significantly increased in both regions 6 and 12 weeks after status epilepticus. Interestingly, immunohistochemical staining showed a predominant increase in the oxidative stress marker 8-OHdG in neurons in both regions after an acute seizure, whereas following status epilepticus, the marker was detected in both neurons and astrocytes. Our findings suggest that SESN3 may contribute to the development and establishment of epilepsy, and could be a potential therapeutic target for more effective treatments.

Original languageAmerican English
Article number109670
JournalNeuropharmacology
Volume238
DOIs
StatePublished - 1 Nov 2023

Bibliographical note

Publisher Copyright:
© 2023

Keywords

  • Antioxidants
  • Epilepsy
  • Oxidative stress
  • ROS
  • Seizure
  • Sestrin 3

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