Antioxidant treatment after epileptogenesis onset prevents comorbidities in rats sensitized by a past stressful event

Epilepsia. 2019 Apr;60(4):648-655. doi: 10.1111/epi.14692. Epub 2019 Mar 13.


Objective: Unresolved past stressful events can induce a state of vulnerability to epilepsy and comorbidities. Using an experimental model of stress-induced vulnerability to depression, we tested whether an antioxidant treatment applied after the onset of epileptogenesis was disease modifying and could prevent the occurrence of comorbidities.

Methods: We used social defeat (SD) to trigger a state of vulnerability in half of the SD-exposed population of rats. One month after SD, we used repeated injections of kainic acid to trigger status epilepticus (SE). One subset of animals was treated after SE during 2 weeks with Tempol, a strong antioxidant. Supradural 24/7 recordings were used to assess the development of epilepsy. We assessed spatial and nonspatial memory as well as a depressionlike profile 6 weeks after SE.

Results: Serum brain-derived neurotrophic factor (BDNF) levels decreased after SD in all animals and recovered to pre-SD levels 1 month later in half of them (SDN group). The other half kept low serum BDNF levels (SDL group). At that stage, SDN and SDL animals do not present a depressionlike profile. The SDL group was more sensitive than the SDN group to epileptogenic conditions. Following SE, the SDL group displayed accelerated epileptogenesis, a depressionlike profile, and severe cognitive deficits as compared to SDN rats. Transient Tempol treatment was disease-modifying, reducing the number of seizures, and prevented the development of comorbidities in the SDL group. Tempol treatment normalized oxidative stress in the SDL group to SDN levels.

Significance: This study illustrates the disease-modifying effect of antioxidant treatment after the onset of epileptogenesis in a population rendered vulnerable by past stressful events. The transient treatment decreased seizure burden and had long-term effects, preventing the occurrence of a depressionlike profile and cognitive deficits. We propose that vulnerability to comorbidities can be reversed after the onset of epilepsy.

Keywords: behavioral stress; cognitive deficits; depression; epilepsy; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Behavior, Animal / drug effects*
  • Comorbidity
  • Convulsants / toxicity
  • Cyclic N-Oxides / pharmacology
  • Epilepsy / chemically induced
  • Epilepsy / psychology*
  • Kainic Acid / toxicity
  • Psychological Distress*
  • Rats
  • Spin Labels
  • Status Epilepticus / chemically induced
  • Status Epilepticus / psychology*


  • Antioxidants
  • Convulsants
  • Cyclic N-Oxides
  • Spin Labels
  • Kainic Acid
  • tempol