title: Temporal and spatial dynamics of nrf2-antioxidant response elements mediated gene targets in cortex and hippocampus after controlled cortical impact traumatic brain injury in mice.
abstract: The pathophysiological importance of oxidative damage after traumatic brain injury (TBI) has been extensively demonstrated. The transcription factor nuclear factor erythoid related factor 2 (Nrf2) mediates antioxidant and cytoprotective genes by binding to antioxidant response elements (ARE) present in nuclear DNA. In this study, we characterized the time course of Nrf2-ARE-mediated expression in the cortex and hippocampus using a unilateral controlled cortical impact model of focal TBI. Ipsilateral hippocampal and cortical tissue was collected for Western-blot protein analysis (n=6/group) or quantitative reverse transcription-polymerase chain reaction for mRNA (n=3/group) at 3, 6, 12, 24, 48, and 72 h or 1 week post-injury. Multiple genes mediated by Nrf2-ARE were altered post-TBI. Specifically, Nrf2 mRNA increased significantly post-TBI at 48 and 72 h in the cortex and at 48 and 72 h and 1 week in the hippocampus with a coincident increase in glial fibrillary acidic protein mRNA, thereby implying this response is likely occurring in astrocytes. Presumably linked to Nrf2 activation, heme-oxygenase-1, nicotinamide adenine dinucleotide phosphate-quinone-oxidoreductase 1, glutathione reductase, and catalase mRNA overlap throughout the post-injury time course. This study demonstrates the first evidence of such changes during the first week after focal TBI and that increases in expression of some Nrf2-ARE-mediated cytoprotective genes are not observed until 24-48 h post-injury. Unfortunately, this does not precede, but rather coincides with, the occurrence of lipid peroxidative damage. This is the first known comparison between the time course of peroxidative damage and that of Nrf2-ARE activation during the first week post-TBI. These results underscore the necessity to discover pharmacological agents to accelerate and amplify Nrf2-ARE-mediated expression early post-TBI.
authors.affiliation: 1 Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine , Lexington, Kentucky.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Miller
authors.forename: Juan A
authors.initials: JA
authors.lastname: Wang
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Buchanan
authors.forename: Edward D
authors.initials: ED
authors.lastname: Hall
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000502:physiology*; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D018390:Gene Targeting / Q000379:methods; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D013997:Time Factors
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse
keywords: 4-hydroxy-2-nonenal; Nrf2; gene expression; lipid peroxidation; oxidative damage; traumatic brain injury