Post-treatment with oxcarbazepine confers potent neuroprotection against transient global cerebral ischemic injury by activating Nrf2 defense pathway.
Animals
Brain Ischemia
/ drug therapy
CA1 Region, Hippocampal
/ drug effects
Catalase
/ metabolism
Cytokines
/ metabolism
Dose-Response Relationship, Drug
Gerbillinae
Glutathione Peroxidase
/ metabolism
Inflammation Mediators
/ metabolism
Male
NF-E2-Related Factor 2
/ metabolism
Neuroprotective Agents
/ administration & dosage
Oxcarbazepine
/ administration & dosage
Oxidative Stress
/ drug effects
Pyramidal Cells
/ drug effects
Superoxide Dismutase
/ metabolism
Voltage-Gated Sodium Channel Blockers
/ administration & dosage
Neuroinflammation
Neuronal death
Nuclear factor erythroid 2-related factor 2
Oxcarbazepine
Oxidative stress
Transient global cerebral ischemia
Journal
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
ISSN: 1950-6007
Titre abrégé: Biomed Pharmacother
Pays: France
ID NLM: 8213295
Informations de publication
Date de publication:
Apr 2020
Apr 2020
Historique:
received:
27
11
2019
revised:
29
12
2019
accepted:
12
01
2020
pubmed:
26
1
2020
medline:
21
11
2020
entrez:
26
1
2020
Statut:
ppublish
Résumé
Oxcarbazepine (OXC), a voltage-gated sodium channel blocker, is an antiepileptic medication and used for the bipolar disorders treatment. Some voltage-gated sodium channel blockers have been demonstrated to display strong neuroprotective properties in models of cerebral ischemia. However, neuroprotective effects and mechanisms of OXC have not yet been reported. Here, we investigated the protective effect of OXC and its mechanisms in the cornu ammonis 1 subfield (CA1) of gerbils subjected to 5 min of transient global cerebral ischemia (tGCI). tGCI led to death of most pyramidal neurons in CA1 at 5 days after ischemia. OXC (100 and 200 mg/kg) was intraperitoneally administered once at 30 min after tGCI. Treatment with 200 mg/kg, not 100 mg/kg OXC, significantly protected CA1 pyramidal neurons from tGCI-induced injury. OXC treatment significantly decreased superoxide anion production, 4-hydroxy-2-nonenal and 8-hydroxyguanine levels in ischemic CA1 pyramidal neurons. In addition, the treatment restored levels of superoxide dismutases, catalase, and glutathione peroxidase. Furthermore, the treatment distinctly inhibited tGCI-induced microglia activation and significantly reduced levels of pro-inflammatory cytokines (interleukin-1β and tumor necrosis factor-α). In particular, OXC treatment significantly enhanced expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream protein heme oxygenase-1 in ischemic CA1. The neuroprotective effects of OXC were abolished by brusatol (an inhibitor of Nrf2). Taken together, these results indicate that post-treatment of OXC can display neuroprotection against brain injuries following ischemic insults. This neuroprotection may be displayed by attenuation of oxidative stress and neuroinflammation, which can be mediated by activation of Nrf2 pathway.
Identifiants
pubmed: 31981945
pii: S0753-3322(20)30040-8
doi: 10.1016/j.biopha.2020.109850
pii:
doi:
Substances chimiques
Cytokines
0
Inflammation Mediators
0
NF-E2-Related Factor 2
0
Neuroprotective Agents
0
Voltage-Gated Sodium Channel Blockers
0
Catalase
EC 1.11.1.6
Glutathione Peroxidase
EC 1.11.1.9
Superoxide Dismutase
EC 1.15.1.1
Oxcarbazepine
VZI5B1W380
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
109850Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The all authors declare that there are no conflicts of interest.