Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis
Background/Aim: Hepatic injury is a hallmark adverse reaction to Valproate (VPA), a common used drug in the management of numerous CNS disorders, including epilepsy. DHA has a myriad of health benefits, including renal- and hepato-protective effects. Unfortunately, however, the underpinnings of such...
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doaj-40072f52108d40e992d03ca4c20197592020-11-24T22:25:58ZengElsevierHeliyon2405-84402016-07-012710.1016/j.heliyon.2016.e00130Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosisAbdalla M. El-Mowafy0Mohamed M. Katary1Chelsey Pye2Ahmed S. Ibrahim3Ahmed A. Elmarakby4Department of Pharmacology, Department of Clinical Biochemistry, Faculty of Pharmacy, Mansoura University, EgyptDepartment of Oral Biology and Pharmacology, Augusta University, Augusta, Georgia 30912, USADepartment of Oral Biology and Pharmacology, Augusta University, Augusta, Georgia 30912, USADepartment of Pharmacology, Department of Clinical Biochemistry, Faculty of Pharmacy, Mansoura University, EgyptDepartment of Oral Biology and Pharmacology, Augusta University, Augusta, Georgia 30912, USABackground/Aim: Hepatic injury is a hallmark adverse reaction to Valproate (VPA), a common used drug in the management of numerous CNS disorders, including epilepsy. DHA has a myriad of health benefits, including renal- and hepato-protective effects. Unfortunately, however, the underpinnings of such liver-pertinent VPA- and DHA-actions remain largely undefined. Accordingly, this study attempted to unveil the cellular and molecular triggers whereby VPA evokes, while DHA abates, hepatotoxicity. Methods: We evaluated activity and/or expression of cellular markers of oxidative stress, inflammation, and apoptosis in rat liver, following treatment with VPA (500 mg/kg/day) with and without concurrent treatment with DHA (250 mg/kg/day) for two weeks. Results and conclusion: VPA promoted hepatic oxidative stress as evidenced by enhancing activity/expression of NADPH-oxidase and its subunits, a ROS-generator, and by accumulation of lipid-peroxides. Moreover, VPA enhanced hepatic phosphorylation/activation of mitogen-activated protein kinase (MAPK), and expression of cyclooxygenase-2(COX-2), as proinflammatory signals. Besides, VPA promoted hepatocellular apoptosis, as attested by enhanced expression of cleaved caspase-9 and increased number of TUNEL-positive hepatocytes. Lastly, VPA upregulated levels of hypoxia-inducible factor-1-alpha (HIF-1α), a multifaceted modulator of hepatocytic biology, and activity of its downstream antioxidant enzyme heme-oxygenase-1(HO-1). These changes were significantly blunted by co-administration of DHA. Our findings demonstrate that VPA activated NADPH-oxidase and HIF-1α to induce oxidative-stress and hypoxia as initiators of hepatic injury. These changes were further aggravated by up-regulation of inflammatory (MAPK and COX-2) and apoptotic cascades, but could be partly lessened by HO-1 activation. Concurrent administration of DHA mitigated all VPA-induced anomalies.http://www.sciencedirect.com/science/article/pii/S2405844016301062BiochemistryCell biologySystems biologyPhysiologyMedicine |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Abdalla M. El-Mowafy Mohamed M. Katary Chelsey Pye Ahmed S. Ibrahim Ahmed A. Elmarakby |
spellingShingle |
Abdalla M. El-Mowafy Mohamed M. Katary Chelsey Pye Ahmed S. Ibrahim Ahmed A. Elmarakby Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis Heliyon Biochemistry Cell biology Systems biology Physiology Medicine |
author_facet |
Abdalla M. El-Mowafy Mohamed M. Katary Chelsey Pye Ahmed S. Ibrahim Ahmed A. Elmarakby |
author_sort |
Abdalla M. El-Mowafy |
title |
Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis |
title_short |
Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis |
title_full |
Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis |
title_fullStr |
Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis |
title_full_unstemmed |
Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis |
title_sort |
novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid dha: role of inflammation and apoptosis |
publisher |
Elsevier |
series |
Heliyon |
issn |
2405-8440 |
publishDate |
2016-07-01 |
description |
Background/Aim: Hepatic injury is a hallmark adverse reaction to Valproate (VPA), a common used drug in the management of numerous CNS disorders, including epilepsy. DHA has a myriad of health benefits, including renal- and hepato-protective effects. Unfortunately, however, the underpinnings of such liver-pertinent VPA- and DHA-actions remain largely undefined. Accordingly, this study attempted to unveil the cellular and molecular triggers whereby VPA evokes, while DHA abates, hepatotoxicity.
Methods: We evaluated activity and/or expression of cellular markers of oxidative stress, inflammation, and apoptosis in rat liver, following treatment with VPA (500 mg/kg/day) with and without concurrent treatment with DHA (250 mg/kg/day) for two weeks.
Results and conclusion: VPA promoted hepatic oxidative stress as evidenced by enhancing activity/expression of NADPH-oxidase and its subunits, a ROS-generator, and by accumulation of lipid-peroxides. Moreover, VPA enhanced hepatic phosphorylation/activation of mitogen-activated protein kinase (MAPK), and expression of cyclooxygenase-2(COX-2), as proinflammatory signals. Besides, VPA promoted hepatocellular apoptosis, as attested by enhanced expression of cleaved caspase-9 and increased number of TUNEL-positive hepatocytes. Lastly, VPA upregulated levels of hypoxia-inducible factor-1-alpha (HIF-1α), a multifaceted modulator of hepatocytic biology, and activity of its downstream antioxidant enzyme heme-oxygenase-1(HO-1). These changes were significantly blunted by co-administration of DHA. Our findings demonstrate that VPA activated NADPH-oxidase and HIF-1α to induce oxidative-stress and hypoxia as initiators of hepatic injury. These changes were further aggravated by up-regulation of inflammatory (MAPK and COX-2) and apoptotic cascades, but could be partly lessened by HO-1 activation. Concurrent administration of DHA mitigated all VPA-induced anomalies. |
topic |
Biochemistry Cell biology Systems biology Physiology Medicine |
url |
http://www.sciencedirect.com/science/article/pii/S2405844016301062 |
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