Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy.
Acetylcysteine
/ pharmacology
Animals
Astrocytes
/ metabolism
Biomarkers
/ metabolism
Case-Control Studies
Cell Count
Cognitive Dysfunction
/ complications
Disease Models, Animal
Electric Stimulation
Epilepsy
/ complications
Glutathione
/ metabolism
HMGB1 Protein
/ blood
Hippocampus
/ metabolism
Humans
Isothiocyanates
/ pharmacology
Male
Neurons
/ metabolism
Oxidative Stress
/ drug effects
Rats
Status Epilepticus
/ complications
Sulfoxides
HMGB1
cognitive deficit
neuroinflammation
neuronal cell loss
spontaneous seizures
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
01 07 2019
01 07 2019
Historique:
received:
12
12
2016
revised:
17
03
2017
accepted:
26
03
2017
pubmed:
31
5
2019
medline:
19
5
2020
entrez:
31
5
2019
Statut:
ppublish
Résumé
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 high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented 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.
Identifiants
pubmed: 31145451
pii: 5506575
doi: 10.1093/brain/awz130
pmc: PMC6598637
doi:
Substances chimiques
Biomarkers
0
HMGB1 Protein
0
Hbp1 protein, rat
0
Isothiocyanates
0
Sulfoxides
0
sulforaphane
GA49J4310U
Glutathione
GAN16C9B8O
Acetylcysteine
WYQ7N0BPYC
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e39Subventions
Organisme : NINDS NIH HHS
ID : R01 NS039587
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS086423
Pays : United States
Commentaires et corrections
Type : RetractedandRepublishedFrom
Informations de copyright
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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