Oxidative stress in experimental traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of death and disability among the young population in the industrialized world. The injury consists of immediate damage to the brain tissue, followed by a secondary response involving inflammation and oxidative stress. No pharmacological treatment is effective and the physical and inflammatory mechanisms are insufficiently understood. Considerable variability exists in the clinical outcome after TBI. Genetic factors have been implicated to affect the posttraumatic inflammatory response. This study was undertaken to explore a possible impact of genetic polymorphism in oxidative stress reactions after experimental TBI, and to determine possible effects of direct physical forces on inflammatory cell activation. TBI was induced using mild focal and penetrating focal brain injury models, in inbred and outbred rat strains and male and female rats. Genetic susceptibility to inflammation in the central nervous system (CNS) was found to be associated to the redox active enzymes iNOS and MnSOD in inflammatory cells, but was not associated with increased neuronal degeneration at 24h. The genetic regulation of oxidative stress vulnerability was corroborated in primary neuronal cultures, where neurons primed in an environment of high susceptibility to inflammatory activity had increased compensatory antioxidative enzymes MnSOD and PRDX5, leading to reduced lipid peroxidation, nitrosylation and degeneration. Humoral stimulation was necessary for iNOS induction in neurons. Gender also affected the inflammatory response. The inflammatory enzyme COX-2 was increased in males compared to females at 24h and 72h and correlated with increased apoptosis at 24h in males, but not neuronal degeneration, astrogliosis, microgliosis or nitrosylation. Direct physical force by shock wave trauma caused an inflammatory activation in two different macrophage cell lines, which did not include iNOS or NO increase. Energy transfer by trauma activated the macrophages directly without humoral mediators, comprising a novel activation mechanism of macrophages. Posttraumatic treatment with the antioxidative compound N-acetylcysteine amide reduced neuronal degeneration, increased MnSOD at 24h and reduced apoptosis at 2h. Levels of migrating macrophages/activated microglia, iNOS, nitrosylation or NFkB were not affected. In summary, our findings demonstrated that genetic factors regulated oxidative stress related inflammation after TBI, macrophages were activated by direct physical forces and an antioxidative drug provided neuroprotection after TBI. Susceptibility to CNS inflammation and oxidative stress are interrelated and should be considered when evaluating novel antioxidative treatments.

List of scientific papers

I. Mattias Günther, Faiez Al Nimer, Caroline Gahm, Fredrik Piehl, Tiit Mathiesen. iNOSmediated secondary inflammatory response differs between rat strains following experimental brain contusion. Acta Neurochir (Wien). 2012 Apr;154(4):689-97.
https://doi.org/10.1007/s00701-012-1297-1

II. Mattias Günther, Faiez Al Nimer, Fredrik Piehl, Stefan Plantman, Mårten Risling and Tiit Mathiesen. Neuronal vulnerability to oxidative stress is affected by genetic polymorphism and related to susceptibility to inflammation in the central nervous system. [Submitted]

III. Mattias Günther, Stefan Plantman, Johan Davidsson, Maria Angéria, Tiit Mathiesen, Mårten Risling. COX-2 regulation and TUNEL-positive cell death differ between genders in the secondary inflammatory response following experimental penetrating focal brain injury in rats. Acta Neurochir (Wien). 2015 Apr;157(4):649-59.
https://doi.org/10.1007/s00701-014-2331-2

IV. Mattias Günther, Stefan Plantman, Caroline Gahm, Anders Sondén, Mårten Risling, Tiit Mathiesen. Shock wave trauma leads to inflammatory response and morphological activation in macrophage cell lines, but does not induce iNOS or NO synthesis. Acta Neurochir (Wien). 2014 Dec;156(12):2365-78.
https://doi.org/10.1007/s00701-014-2243-1

V. Mattias Günther, Johan Davidsson, Stefan Plantman, Svante Norgren, Tiit Mathiesen, Mårten Risling. Neuroprotective Effects of N-acetylcysteine Amide on Experimental Focal Penetrating Brain Injury in rats. J Clinical Neuroscience. [Accepted]
https://doi.org/10.1016/j.jocn.2015.03.025