Abstract
Traumatic brain injury (TBI) leads to a deleterious and multifactorial secondary inflammatory response in the brain. Oxidative stress from the inflammation likely contributes to the brain damage although it is unclear to which extent. A largely unexplored approach is to consider phenotypic regulation of oxidative stress levels. Genetic polymorphism influences inflammation in the central nervous system and it is possible that the antioxidative response differs between phenotypes and affects the severity of the secondary injury. We therefore compared the antioxidative response in inbred rat strains Dark Agouti (DA) to Piebald Viral Glaxo (PVG). DA has high susceptibility to inflammatory challenges and PVG is protected. Primary neuronal cell cultures were exposed to peroxynitrite (ONOO-), nitric oxide (NO), superoxide (O2-) and 4-hydroxynonenal (4-HNE). Our findings demonstrated a phenotypic control of the neuronal antioxidative response, specific to manganese superoxide dismutase (MnSOD). DA neurons had increased levels of MnSOD, equal levels of peroxiredoxin 5, decreased oxidative stress markers 3-Nitrotyrosine and 4-HNE and decreased neuronal death detected by lactate dehydrogenase release after 24h, and higher oxidative stress levels by CellROX than PVG after 2h. It is possible that DA neurons had a phenotypic adaptation to a fiercer inflammatory environment. Peroxynitrite was confirmed as the most powerful oxidative damage mediator, while 4-HNE caused few oxidative effects. iNOS was not induced, suggesting that inflammatory, while not oxidative stimulation was required. These findings indicate that phenotypic antioxidative regulation affects the secondary inflammation, which should be considered in future individualized treatments and when evaluating antioxidative pharmacological interventions.
Significance Statement Neurotrauma leads to inflammation and oxidative stress in the brain. The outcome differs between individuals and it is largely unknown what causes this diversity. It is possible that the brain phenotype is linked to oxidative stress levels, and that some individuals acquire less oxidative stress than others. We therefore tested the oxidative stress reaction patterns in rat neurons from two strains with different susceptibility to inflammation. We found that the phenotypes have different regulation of antioxidative enzymes and oxidative stress. While further studies are needed to corroborate the findings in vivo, it is a proof of concept of genetic regulation of direct oxidative stress, which may impact outcome after TBI and interact with future antioxidative treatment trials.
Footnotes
Authors report no conflict of interest.
The study was funded by the Swedish Defense and ALF Stockholms Läns Landsting.
Jump to comment: