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Int J Mol Sci. 2019 Sep 30;20(19). pii: E4862. doi: 10.3390/ijms20194862.

CDDO-Me Attenuates Vasogenic Edema and Astroglial Death by Regulating NF-κB p65 Phosphorylations and Nrf2 Expression Following Status Epilepticus.

Kim MJ1,2, Park H3,4, Choi SH5,6, Kong MJ7,8, Kim JE9,10, Kang TC11,12.

Author information

1
Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea. kmj4180@hallym.ac.kr.
2
Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea. kmj4180@hallym.ac.kr.
3
Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea. M19050@hallym.ac.kr.
4
Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea. M19050@hallym.ac.kr.
5
Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea. 20161239@hallym.ac.kr.
6
Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea. 20161239@hallym.ac.kr.
7
Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.
8
Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea.
9
Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea. jieunkim@hallym.ac.kr.
10
Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea. jieunkim@hallym.ac.kr.
11
Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea. zolim@hallym.ac.kr.
12
Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea. zolim@hallym.ac.kr.

Abstract

2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid that has anti-inflammatory, antioxidant, and neuroprotective activities. In the present study, we evaluate the effects of CDDO-Me on serum extravasation and astroglial death in the rat piriform cortex (PC) induced by status epilepticus (a prolonged seizure activity, SE) in order to propose an underlying pharmacological mechanism of CDDO-Me and its availability for treatment of vasogenic edema. CDDO-Me effectively mitigated serum extravasation and a massive astroglial loss in the PC following SE. CDDO-Me abrogated tumor necrosis factor-α (TNF-α) synthesis in activated microglia by inhibiting nuclear factor-κB (NF-κB) p65 serine 276 phosphorylation. CDDO-Me also abolished NF-κB threonine 435 phosphorylation in endothelial cells and TNF-α-mediated-phosphatidylinositol-3-kinase (PI3K)/AKT/endothelial nitric oxide synthase (eNOS) signaling cascades, which trigger vasogenic edema following SE. Furthermore, CDDO-Me increased astroglial viability via the up-regulation of nuclear factor-erythroid 2-related factor 2 (Nrf2) expression. Therefore, our findings suggest that CDDO-Me may ameliorate SE-induced vasogenic edema formation by regulating NF-κB p65 phosphorylations in microglia as well as endothelial cells and enhancing Nrf2 expression in astrocytes, respectively.

KEYWORDS:

AKT; BBB; PI3K; SMI-71; astrocyte; eNOS; microglia; seizure

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