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

Biomedicine & Pharmacotherapy

Joon Ha Park¹  Dae Won Kim²  Sungwoo Ryoo³  Ji Hyeon Ahn⁴  Jun Hwi Cho⁵  Yoonsoo Park⁵  Myoung Cheol Shin⁵  Young-Myeong Kim⁶  Jae-Chul Lee⁷  Cheol Woo Park⁷  Young Eun Park⁷  Bora Kim⁷  Moo-Ho Won⁷  Tae-Kyeong Lee⁷ 

[1] Corresponding authors at: Department of Neurobiology, School of Medicine, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon, Gangwon, 24341 Republic of Korea.;Department of Biochemistry and Molecular Biology, and Research Institute of Oral Sciences, College of Dentistry, Gangnung-Wonju National University, Gangneung, Gangwon 25457, Republic of Korea;Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea;Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea;Department of Emergency Medicine, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea;Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea;Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea;

关键词: Nuclear factor erythroid 2-related factor 2;    Neuroinflammation;    Neuronal death;    Oxcarbazepine;    Oxidative stress;    Transient global cerebral ischemia;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown