Post-treatment with oxcarbazepine confers potent neuroprotection against transient global cerebral ischemic injury by activating Nrf2 defense pathway.

Abstract

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.

• Authors: Cheol Woo Park, Ji Hyeon Ahn, Tae-Kyeong Lee, Young Eun Park, Bora Kim, Jae-Chul Lee, Dae Won Kim, Myoung Cheol Shin, Yoonsoo Park, Jun Hwi Cho, Sungwoo Ryoo, Young-Myeong Kim, Moo-Ho Won, Joon Ha Park
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 124 Pg. 109850 (Apr 2020) ISSN: 1950-6007 [Electronic] France
• PMID: 31981945 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Cytokines
• Inflammation Mediators
• NF-E2-Related Factor 2
• Neuroprotective Agents
• Voltage-Gated Sodium Channel Blockers
• Catalase
• Glutathione Peroxidase
• Superoxide Dismutase
• Oxcarbazepine

Topics

• Animals
• Brain Ischemia (drug therapy, physiopathology)
• CA1 Region, Hippocampal (drug effects, pathology)
• 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, pharmacology)
• Oxcarbazepine (administration & dosage, pharmacology)
• Oxidative Stress (drug effects)
• Pyramidal Cells (drug effects)
• Superoxide Dismutase (metabolism)
• Voltage-Gated Sodium Channel Blockers (administration & dosage, pharmacology)