Nrf2–ARE activator carnosic acid decreases mitochondrial dysfunction, oxidative damage and neuronal cytoskeletal degradation following traumatic brain injury in mice

• Published in: Experimental neurology Vol. 264; pp. 103 - 110
• Main Authors: Miller, Darren M., Singh, Indrapal N., Wang, Juan A., Hall, Edward D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2015
• Subjects: 4-Hydroxy-2-nonenal; Abietanes - therapeutic use; Adenosine Diphosphate - metabolism; Aldehydes - metabolism; Analysis of Variance; Animals; Antioxidants - therapeutic use; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain Injuries - complications; Brain Injuries - drug therapy; Cytoskeleton - drug effects; Cytoskeleton - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Lipid peroxidation; Lipid Peroxidation - drug effects; Male; Mice; Mitochondria; Mitochondrial Diseases - drug therapy; Mitochondrial Diseases - etiology; Nrf2; Oxidative damage; Oxidative Stress - drug effects; Plant Extracts - therapeutic use; Succinic Acid - metabolism; Traumatic brain injury; Lipid peroxidation; 4-Hydroxy-2-nonenal; Mitochondria; Traumatic brain injury; Nrf2; Oxidative damage
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2014.11.008

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 15min post-TBI reduced cortical lipid peroxidation, protein nitration, and cytoskeletal breakdown markers in a dose-dependent manner at 48h 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.