Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis

Abdalla M. El-Mowafy, Mohamed M. Katary, Chelsey Pye, Ahmed Salah Ibrahim, Ahmed Abdelrazik Elmarakby

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere00130
JournalHeliyon
Volume2
Issue number7
DOIs
StatePublished - Jul 1 2016

Fingerprint

Omega-3 Fatty Acids
Valproic Acid
Apoptosis
Inflammation
Liver
Wounds and Injuries
Hypoxia-Inducible Factor 1
Heme Oxygenase-1
Oxidative Stress
NADPH Oxidase
Cyclooxygenase 2
Caspase 9
Lipid Peroxides
Mitogen-Activated Protein Kinase 1
In Situ Nick-End Labeling
Insurance Benefits
Mitogen-Activated Protein Kinases
Hepatocytes
Epilepsy
Up-Regulation

Keywords

  • Biochemistry
  • Cell biology
  • Medicine
  • Physiology
  • Systems biology

ASJC Scopus subject areas

  • General

Cite this

Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA : role of inflammation and apoptosis. / El-Mowafy, Abdalla M.; Katary, Mohamed M.; Pye, Chelsey; Ibrahim, Ahmed Salah; Elmarakby, Ahmed Abdelrazik.

In: Heliyon, Vol. 2, No. 7, e00130, 01.07.2016.

Research output: Contribution to journalArticle

@article{9906f0abd9474530a23796d9dfcf1c5d,
title = "Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis",
abstract = "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.",
keywords = "Biochemistry, Cell biology, Medicine, Physiology, Systems biology",
author = "El-Mowafy, {Abdalla M.} and Katary, {Mohamed M.} and Chelsey Pye and Ibrahim, {Ahmed Salah} and Elmarakby, {Ahmed Abdelrazik}",
year = "2016",
month = "7",
day = "1",
doi = "10.1016/j.heliyon.2016.e00130",
language = "English (US)",
volume = "2",
journal = "Heliyon",
issn = "2405-8440",
publisher = "Elsevier BV",
number = "7",

}

TY - JOUR

T1 - Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA

T2 - role of inflammation and apoptosis

AU - El-Mowafy, Abdalla M.

AU - Katary, Mohamed M.

AU - Pye, Chelsey

AU - Ibrahim, Ahmed Salah

AU - Elmarakby, Ahmed Abdelrazik

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

KW - Biochemistry

KW - Cell biology

KW - Medicine

KW - Physiology

KW - Systems biology

UR - http://www.scopus.com/inward/record.url?scp=84981361164&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84981361164&partnerID=8YFLogxK

U2 - 10.1016/j.heliyon.2016.e00130

DO - 10.1016/j.heliyon.2016.e00130

M3 - Article

AN - SCOPUS:84981361164

VL - 2

JO - Heliyon

JF - Heliyon

SN - 2405-8440

IS - 7

M1 - e00130

ER -