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      Curcumin attenuates hypoxic-ischemic brain injury in neonatal rats through induction of nuclear factor erythroid-2-related factor 2 and heme oxygenase-1

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          Abstract

          Curcumin has previously demonstrated anti-inflammatory, anti-infective and immuno-suppressive effects. In the present study, whether the attenuating effects of curcumin against hypoxic-ischemic brain injury in neonatal rats are mediated via nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was investigated. A model of hypoxic-ischemic brain injury was created using 1-week-old Sprague Dawley rats (weight, 52±1 g). The model rats were treated with 150 mg/kg curcumin by gavage for 3 days. Malondialdehyde levels, and superoxide dismutase and caspase-3 activities were assayed using commercial kits and western blot analysis was used to measure inducible nitric oxide synthase (iNOS), Nrf2 and HO-1 expression levels. Treatment with curcumin effectively reduced the brain injury score, increased myelin basic protein (MBP) expression and increased the quantity of neuronal cells in neonatal rats with hypoxic-ischemic brain injury. Furthermore, treatment with curcumin significantly attenuated the changes in SOD activity and MDA levels and suppressed the iNOS protein expression induced in neonatal rats by hypoxic-ischemic brain injury. Treatment with curcumin significantly increased Nrf2 and HO-1 expression in the neonatal rats with hypoxic-ischemic brain injury. The present study indicated that curcumin attenuates hypoxic-ischemic brain injury in neonatal rats through the induction of Nrf2 and HO-1.

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          Most cited references31

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          Activated AMPK boosts the Nrf2/HO-1 signaling axis—A role for the unfolded protein response

          In light of the emerging interplay between redox and metabolic signaling pathways we investigated the potential cross talk between nuclear factor E2-related factor 2 (Nrf2) and AMP-activated kinase (AMPK), central regulators of the cellular redox and energy balance, respectively. Making use of xanthohumol (XN) as an activator of both the AMPK and the Nrf2 signaling pathway we show that AMPK exerts a positive influence on Nrf2/heme oxygenase (HO)-1 signaling in mouse embryonic fibroblasts. Genetic ablation and pharmacological inhibition of AMPK blunts Nrf2-dependent HO-1 expression by XN already at the mRNA level. XN leads to AMPK activation via interference with mitochondrial function and activation of liver kinase B1 as upstream AMPK kinase. The subsequent AMPK-mediated enhancement of the Nrf2/HO-1 response does not depend on inhibition of the mammalian target of rapamycin, inhibition of glycogen synthase kinase 3β, or altered abundance of Nrf2 (total and nuclear). However, reduced endoplasmic reticulum stress was identified and elaborated as a step in the AMPK-augmented Nrf2/HO-1 response. Overall, we shed more light on the hitherto incompletely understood cross talk between the LKB1/AMPK and the Nrf2/HO-1 axis revealing for the first time involvement of the unfolded protein response as an additional player and suggesting tight cooperation between signaling pathways controlling cellular redox, energy, or protein homeostasis.
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            Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13.

            To address the underlying mechanisms by which curcumin facilitates M2 phenotype polarization of macrophages and its roles in the protective effects during experimental autoimmune myocarditis (EAM).
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              Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model.

              Hypoxia-ischemia (HI) brain injury is a major cause of neuronal cell death especially apoptosis in the perinatal period. This study was designated to examine the effect of hydrogen therapy on apoptosis in an established neonatal HI rat pup model. Seven-day-old rat pups were subjected to left common carotid artery ligation and then 90 min hypoxia (8% oxygen at 37 degrees C). Immediately after HI insult, pups were placed into a chamber filled with 2% H2 for 30 min, 60 min, or 120 min, respectively. 24 h after 2% H2 therapy, the pups were decapitated and brain injury was assessed by 2,3,5-triphenyltetrazoliumchloride (TTC), Nissl, and TUNEL staining, as well as caspase-3, caspase-12 activities in the cortex and hippocampus. H2 treatment in a duration-dependent manner significantly reduced the number of positive TUNEL cells and suppressed caspase-3 and -12 activities. These results indicated H2 administration after HI appeared to provide brain protection via inhibition of neuronal apoptosis.
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                Author and article information

                Journal
                Exp Ther Med
                Exp Ther Med
                ETM
                Experimental and Therapeutic Medicine
                D.A. Spandidos
                1792-0981
                1792-1015
                August 2017
                27 June 2017
                27 June 2017
                : 14
                : 2
                : 1512-1518
                Affiliations
                [1 ]Department of Rehabilitation Medicine, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
                [2 ]Department of Spleen and Stomach, Affiliated Hospital of Shandong University of TCM, Jinan, Shandong 250013, P.R. China
                [3 ]Department of Cadres and Health Care, The Second Affiliated Hospital of Shandong University of TCM, Jinan, Shandong 250001, P.R. China
                Author notes
                Correspondence to: Mr. Jie Su, Department of Cadres and Health Care, The Second Affiliated Hospital of Shandong University of TCM, 1 West Qingnian Road, Central Road, Jinan, Shandong 250001, P.R. China, E-mail: jiesuss123@ 123456163.com
                Article
                ETM-0-0-4683
                10.3892/etm.2017.4683
                5526188
                28781627
                a732e4e1-de7a-4646-8fb5-fd83f687af47
                Copyright: © Cui et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 29 October 2015
                : 03 March 2017
                Categories
                Articles

                Medicine
                curcumin,hypoxic-ischemic brain injury,nuclear factor erythroid-2-related factor 2,heme oxygenase-1

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