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: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Department of Clinical Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt; Department of Pharmacology, Faculty of Pharmaceutical Sciences and Industries, Future University, Egypt.
authors.forename: Abdalla M
authors.initials: AM
authors.lastname: El-Mowafy
authors.affiliation: Department of Oral Biology and Pharmacology, Augusta University, Augusta, Georgia 30912, USA; Department of Pharmacology, Faculty of Pharmacy, Damanhur University, Egypt.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Katary
authors.affiliation: Department of Oral Biology and Pharmacology, Augusta University, Augusta, Georgia 30912, USA.
authors.forename: Chelsey
authors.initials: C
authors.lastname: Pye
authors.affiliation: Department of Pharmacology, Department of Clinical Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt; Department of Oral Biology and Pharmacology, Augusta University, Augusta, Georgia 30912, USA.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Ibrahim
authors.affiliation: Department of Oral Biology and Pharmacology, Augusta University, Augusta, Georgia 30912, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Elmarakby
keywords: Biochemistry; Cell biology; Medicine; Physiology; Systems biology