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 (ARE) 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 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 minutes post-TBI reduced cortical lipid peroxidation, protein nitration, and cytoskeletal breakdown markers in a dose-dependent manner at 48 hours 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 8 hours 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.

Time courses of post-injury mitochondrial oxidative damage and respiratory dysfunction and neuronal cytoskeletal degradation in a rat model of focal traumatic brain injury

“…These findings of a surprisingly delayed peak in secondary injury, suggest that the therapeutic window and needed treatment duration for certain antioxidant treatment strategies following CCI-TBI in rodents may be longer than previously believed. Indeed, This is supported by our past therapeutic window studies in the mouse CCI-TBI paradigm in which we used attenuation of calpain-mediated α-spectrin degradation as a neuroprotective endpoint with which we observed significant cytoskeletal protective efficacy with the LP inhibitor U-83836E (Mustafa et al, 2011), the cyclosporine A analog NIM811 (Mbye et al, 2009) and the Nrf2-antioxidant response element activator carnosic acid (Miller et al, 2015) even when dosing was not initiated until as much as 12h after TBI. Additionally, in the rat CCI-TBI paradigm we observed a significant increase in cortical spared tissue at one week post-injury could be achieved with cyclosporine A treatment even when treatment initiation was delayed for as long as 8h (Sullivan et al, 2011).…”

Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways

“…An endogenous cytoprotective defense system protects the brain by balancing ROS and antioxidant/defense enzymes [50]. The pleiotropic transcription factor Nrf2 plays a key role in adjusting the inducible cytoprotective response by activating AREs [5, 51, 52]. Under physiologic conditions, Nrf2 binds with its negative regulator, Keap 1, in the cytoplasm [53].…”

Ryanodine Receptor 2 Plays a Critical Role in Spinal Cord Injury via Induction of Oxidative Stress

“…Mitochondrial dysfunction is an important pathophysiological process that is associated with various diseases. Especially, mitochondrial dysfunction is believed to be an important contributor to SCI [25][26][27]. In addition, ER stress participates in various types of damage after traumatic injury of spinal cord [28][29][30].…”