title: Nrf2-ARE activator carnosic acid decreases mitochondrial dysfunction, oxidative damage and neuronal cytoskeletal degradation following traumatic brain injury in mice.
abstract: The importance of free radical-induced oxidative damage after traumatic brain injury (TBI) has been well documented. Despite multiple clinical trials with radical-scavenging antioxidants that are neuroprotective in TBI models, none is approved for acute TBI patients. As an alternative antioxidant target, Nrf2 is a transcription factor that activates expression of antioxidant and cytoprotective genes by binding to antioxidant response elements (AREs) within DNA. Previous research has shown that neuronal mitochondria are susceptible to oxidative damage post-TBI, and thus the current study investigates whether Nrf2-ARE activation protects mitochondrial function when activated post-TBI. It was hypothesized that administration of carnosic acid (CA) would reduce oxidative damage biomarkers in the brain tissue and also preserve cortical mitochondrial respiratory function post-TBI. A mouse controlled cortical impact (CCI) model was employed with a 1.0mm cortical deformation injury. Administration of CA at 15 min post-TBI reduced cortical lipid peroxidation, protein nitration, and cytoskeletal breakdown markers in a dose-dependent manner at 48 h post-injury. Moreover, CA preserved mitochondrial respiratory function compared to vehicle animals. This was accompanied by decreased oxidative damage to mitochondrial proteins, suggesting the mechanistic connection of the two effects. Lastly, delaying the initial administration of CA up to 8h post-TBI was still capable of reducing cytoskeletal breakdown, thereby demonstrating a clinically relevant therapeutic window for this approach. This study demonstrates that pharmacological Nrf2-ARE induction is capable of neuroprotective efficacy when administered after TBI.
authors.affiliation: Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY 40536-0509, USA; Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY 40536-0509, USA.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Miller
authors.affiliation: Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY 40536-0509, USA; Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY 40536-0509, USA.
authors.forename: Indrapal N
authors.initials: IN
authors.lastname: Singh
authors.affiliation: Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY 40536-0509, USA.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Wang
authors.affiliation: Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY 40536-0509, USA; Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY 40536-0509, USA. Electronic address: edhall@uky.edu.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Hall
mesh_terms: D045784:Abietanes / Q000627:therapeutic use*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000150:complications* / Q000188:drug therapy; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000209:etiology*; D018384:Oxidative Stress / Q000187:drug effects*; D010936:Plant Extracts / Q000627:therapeutic use*; D019802:Succinic Acid / Q000378:metabolism
chemical_list: D045784:Abietanes; D000447:Aldehydes; D000975:Antioxidants; D010936:Plant Extracts; D000244:Adenosine Diphosphate; D019802:Succinic Acid; C027576:4-hydroxy-2-nonenal; C018381:salvin
keywords: 4-Hydroxy-2-nonenal; Lipid peroxidation; Mitochondria; Nrf2; Oxidative damage; Traumatic brain injury