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.
Highlights
Vasogenic edema results from the increased capillary permeability due to breakdown in intact brain–blood barrier (BBB) that is important for the maintenance of brain homeostasis [1,2]
The piriform cortex (PC) is a suitable site to evaluate the effects of CDDO-Me on vasogenic edema formation and the related events following SE
Since the up-regulation of tumor necrosis factor-α (TNF-α) expression in activated microglia plays an important role in SE-induced vasogenic edema formation [1,12,13,23], we investigated whether CDDO-Me affects microglial TNF-α expression induced by SE
Summary
Vasogenic edema results from the increased capillary permeability due to breakdown in intact brain–blood barrier (BBB) that is important for the maintenance of brain homeostasis [1,2]. The leakage of albumin from blood into brain tissue activates microglia and results in the production of inflammatory mediators [4,5], astrocytes and blood-derived monocytes are involved in pro-inflammatory reactions [6,7]. These neuroinflammatory responses to vasogenic edema formation are the risk factors of pharmacoresistant temporal lobe epilepsy that is uncontrolled by conventional antiepileptic drugs [8]. The blockade or attenuation of vasogenic edema formation may be one of the important therapeutic strategies for the prevention of secondary complications following various brain insults including status epilepticus (SE, a prolonged seizure activity)
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