Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy

Alberto Pauletti, Gaetano Terrone, Tawfeeq Shekh-Ahmad, Alessia Salamone, Teresa Ravizza, Massimo Rizzi, Anna Pastore, Rosaria Pascente, Li Ping Liang, Bianca R. Villa, Silvia Balosso, Andrey Y. Abramov, Erwin A. Van Vliet, Ennio Del Giudice, Eleonora Aronica, Daniel J. Antoine, Manisha Patel, Matthew C. Walker, Annamaria Vezzani

Research output: Contribution to journalArticle

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Abstract

Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease - preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of disulfide high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented disulfide HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.
Original languageEnglish
Pages (from-to)1885-1899
Number of pages15
JournalBrain
Volume140
Issue number7
DOIs
Publication statusPublished - Jul 1 2017

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Epilepsy
Oxidative Stress
Seizures
Status Epilepticus
Pharmaceutical Preparations
Drug Combinations
Disulfides
Therapeutics
Neurons
Acetylcysteine
Therapeutic Uses
Astrocytes
Glutathione
Disease Progression
Hippocampus
Antioxidants
Biomarkers
Incidence
Wounds and Injuries
Brain

Keywords

  • cognitive deficit
  • HMGB1
  • neuroinflammation
  • neuronal cell loss
  • spontaneous seizures

Cite this

Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. / Pauletti, Alberto; Terrone, Gaetano; Shekh-Ahmad, Tawfeeq; Salamone, Alessia; Ravizza, Teresa; Rizzi, Massimo; Pastore, Anna; Pascente, Rosaria; Liang, Li Ping; Villa, Bianca R.; Balosso, Silvia; Abramov, Andrey Y.; Van Vliet, Erwin A.; Del Giudice, Ennio; Aronica, Eleonora; Antoine, Daniel J.; Patel, Manisha; Walker, Matthew C.; Vezzani, Annamaria.

In: Brain, Vol. 140, No. 7, 01.07.2017, p. 1885-1899.

Research output: Contribution to journalArticle

Pauletti, A, Terrone, G, Shekh-Ahmad, T, Salamone, A, Ravizza, T, Rizzi, M, Pastore, A, Pascente, R, Liang, LP, Villa, BR, Balosso, S, Abramov, AY, Van Vliet, EA, Del Giudice, E, Aronica, E, Antoine, DJ, Patel, M, Walker, MC & Vezzani, A 2017, 'Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy', Brain, vol. 140, no. 7, pp. 1885-1899. https://doi.org/10.1093/brain/awx117
Pauletti A, Terrone G, Shekh-Ahmad T, Salamone A, Ravizza T, Rizzi M et al. Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain. 2017 Jul 1;140(7):1885-1899. https://doi.org/10.1093/brain/awx117
Pauletti, Alberto ; Terrone, Gaetano ; Shekh-Ahmad, Tawfeeq ; Salamone, Alessia ; Ravizza, Teresa ; Rizzi, Massimo ; Pastore, Anna ; Pascente, Rosaria ; Liang, Li Ping ; Villa, Bianca R. ; Balosso, Silvia ; Abramov, Andrey Y. ; Van Vliet, Erwin A. ; Del Giudice, Ennio ; Aronica, Eleonora ; Antoine, Daniel J. ; Patel, Manisha ; Walker, Matthew C. ; Vezzani, Annamaria. / Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. In: Brain. 2017 ; Vol. 140, No. 7. pp. 1885-1899.
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