The Role of Reactive Oxygen Species in the Pathogenesis of Traumatic Brain Injury

In previous studies, the authors showed that the nitrone radical scavenger α-phenyl-N- tert-butyl nitrone (PBN) and its sulfo-derivative, 2-sulfo-phenyl-N- tert-butyl nitrone (S-PBN), attenuated cognitive disturbance and reduced tissue damage after traumatic brain injury (TBI) in rats. In the current study, the production of reactive oxygen species (ROS) after TBI was monitored with microdialysis and the 4-hydroxybenzoic acid (4-HBA) trapping method. A single dose of PBN (30 mg/kg) or an equimolar dose of S-PBN (47 mg/kg) was administered intravenously 30 minutes before a controlled cortical contusion injury in rats. Plasma and brain tissue drug concentrations were analyzed at the end of the microdialysis experiment (3 hours after injury) and, in a separate experiment with S-PBN, at 30 and 60 minutes after injury. Traumatic brain injury caused a significant increase in ROS formation that lasted for 60 minutes after the injury as evidenced by increased 3,4-dihydroxybenzoic acid (3,4-DHBA) concentrations in the dialysate. PBN and S-PBN equally and significantly attenuated the posttraumatic increase in 3,4-DHBA formation. High PBN concentrations were found bilaterally in brain tissue up to 3 hours after injury. In contrast, S-PBN was rapidly cleared from the circulation and was not detectable in brain at 30 minutes after injury or at any later time point. The results suggest that scavenging of ROS after TBI may contribute to the neuroprotective properties observed with nitrone spin-trapping agents. S-PBN, which remained undetectable even in traumatized brain tissue, reduced ROS production to the same extent as PBN that readily crossed the blood–brain barrier. This finding supports an important role for ROS production at the blood–endothelial interface in TBI.

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Attenuation of Ischemia-Induced Mouse Brain Injury by SAG, a Redox-Inducible Antioxidant Protein

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200106000-00010 ◽

2001 ◽

Vol 21 (6) ◽

pp. 722-733 ◽

Cited By ~ 44

Author(s):

Guo-Yuan Yang ◽

Li Pang ◽

Hai-Liang Ge ◽

Mingjia Tan ◽

Wen Ye ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Brain Injury ◽

Mouse Brain ◽

Ischemia Reperfusion ◽

Reactive Oxygen ◽

Model Systems ◽

Oxygen Species ◽

Antioxidant Protein

Cerebral ischemia resulting from a disruption of blood flow to the brain initiates a cascade of events that causes neuron death and leads to neurologic dysfunction. Reactive oxygen species are thought, at least in part, to mediate this disease process. The authors recently cloned and characterized an antioxidant protein, SAG (sensitive to apoptosis gene), that is redox inducible and protects cells from apoptosis induced by redox agents in a number of in vitro cell model systems. This study reports a neuroprotective role of SAG in ischemia/reperfusion-induced brain injury in an in vivo mouse model. SAG was expressed at a low level in brain tissue and was inducible after middle cerebral artery occlusion with peak expression at 6 to 12 hours. At the cellular level, SAG was mainly expressed in the cytoplasm of neurons and astrocytes, revealed by double immunofluorescence. An injection of recombinant adenoviral vector carrying human SAG into mouse brain produced an overexpression of SAG protein in the injected areas. Transduction of AdCMVSAG (wild-type), but not AdCMVmSAG (mutant), nor the AdCMVlacZ control, protected brain cells from ischemic brain injury, as evidenced by significant reduction of the infarct areas where SAG was highly expressed. The result suggests a rather specific protective role of SAG in the current in vivo model. Mechanistically, SAG overexpression decreased reactive oxygen species production and reduced the number of apoptotic cells in the ischemic areas. Thus, antioxidant SAG appears to protect against reactive oxygen species–induced brain damage in mice. Identification of SAG as a neuroprotective molecule could lead to potential stroke therapies.

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New Insights into Oxidative Damage and Iron Associated Impairment in Traumatic Brain Injury

Current Pharmaceutical Design ◽

10.2174/1381612825666191111153802 ◽

2020 ◽

Vol 25 (45) ◽

pp. 4737-4746

Author(s):

Nicolas Toro-Urrego ◽

Liliana F. Turner ◽

Marco F. Avila-Rodriguez

Keyword(s):

Reactive Oxygen Species ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Oxidative Damage ◽

Brain Tissue ◽

Reactive Oxygen ◽

Iron Chelators ◽

Oxygen Species ◽

Underlying Mechanisms ◽

The Brain

: Traumatic Brain Injury is considered one of the most prevalent causes of death around the world; more than seventy millions of individuals sustain the condition per year. The consequences of traumatic brain injury on brain tissue are complex and multifactorial, hence, the current palliative treatments are limited to improve patients’ quality of life. The subsequent hemorrhage caused by trauma and the ongoing oxidative process generated by biochemical disturbances in the in the brain tissue may increase iron levels and reactive oxygen species. The relationship between oxidative damage and the traumatic brain injury is well known, for that reason, diminishing factors that potentiate the production of reactive oxygen species have a promissory therapeutic use. Iron chelators are molecules capable of scavenging the oxidative damage from the brain tissue and are currently in use for ironoverload- derived diseases. : Here, we show an updated overview of the underlying mechanisms of the oxidative damage after traumatic brain injury. Later, we introduced the potential use of iron chelators as neuroprotective compounds for traumatic brain injury, highlighting the action mechanisms of iron chelators and their current clinical applications.

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