iNOS-mediated secondary inflammatory response differs between rat strains following experimental brain contusion
- 217 Downloads
Nitric oxide is a key mediator of post-traumatic inflammation in the brain. We examined the expressions of iNOS, nNOS, and eNOS in inbred DA and PVGa rat strains where DA is susceptible to autoimmune neuroinflammation and PVGa-resistant.
Parietal contusions using a weight drop model were produced in five rats per genotype. After 24 h, the brains were removed and analyzed using a range of immunohistochemical methods.
PVGa presented significantly increased iNOS expression in infiltrating inflammatory cells in the perilesional area compared to DA (p < 0.05). The amount of w3/13-positive infiltrating inflammatory cells did not differ between strains. eNOS and nNOS expression did not differ between strains. iNOS-positive cells coexpressed neuronal (NeuN), macrophage (ED-1), and leucocyte (w3/13) markers. MnSOD was significantly increased in PVGa (p < 0.05). 3-Nitrotyrosine, a measure of peroxynitrite levels, and fluoro-jade stained neuronal degeneration, did not differ between strains.
Two inbred rat strains with genetically determined differences in susceptibility to develop autoimmune disease displayed different levels of the inflammatory and anti-inflammatory mediators iNOS and MnSOD, indicating genetic regulation. Interestingly, the increased levels of iNOS did not lead to elevated expression of the neuronal cell-death marker fluoro-jade. The increased iNOS expression was correlated with increased expression of superoxide scavenger MnSOD. Excessive peroxynitrite formation was probably prevented by limitation of available superoxide. Subsequently, the higher expression of potentially deleterious iNOS in PVGa did not result in increased neuronal death.
KeywordsNeurotrauma Neuroinflammation TBI Nitric oxide synthase Peroxynitrite Manganese superoxide dismutase Dark Agouti Piebald Virol Glaxo
Conflicts of interest
- 1.(1999) Consensus conference. Rehabilitation of persons with traumatic brain injury. NIH Consensus Development Panel on Rehabilitation of Persons With Traumatic Brain Injury. JAMA 282:974–983Google Scholar
- 14.Gahm C, Danilov A, Holmin S, Wiklund PN, Brundin L, Mathiesen T (2005) Reduced neuronal injury after treatment with NG-nitro-L-arginine methyl ester (L-NAME) or 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) following experimental brain contusion. Neurosurgery 57:1272–1281, discussion 1272–1281PubMedCrossRefGoogle Scholar
- 25.Keller JN, Kindy MS, Holtsberg FW, St Clair DK, Yen HC, Germeyer A, Steiner SM, Bruce-Keller AJ, Hutchins JB, Mattson MP (1998) Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci 18:687–697PubMedGoogle Scholar
- 26.Khan M, Im YB, Shunmugavel A, Gilg AG, Dhindsa RK, Singh AK, Singh I (2009) Administration of S-nitrosoglutathione after traumatic brain injury protects the neurovascular unit and reduces secondary injury in a rat model of controlled cortical impact. J Neuroinflamm 6 Google Scholar
- 39.Sinz EH, Kochanek PM, Dixon CE, Clark RS, Carcillo JA, Schiding JK, Chen M, Wisniewski SR, Carlos TM, Williams D, DeKosky ST, Watkins SC, Marion DW, Billiar TR (1999) Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice. J Clin Invest 104:647–656PubMedCrossRefGoogle Scholar
- 44.Terpolilli NA, Zweckberger K, Trabold R, Schilling L, Schinzel R, Tegtmeier F, Plesnila N (2009) The novel nitric oxide synthase inhibitor 4-amino-tetrahydro-L-biopterine prevents brain edema formation and intracranial hypertension following traumatic brain injury in mice. J Neurotrauma 26:1963–1975PubMedCrossRefGoogle Scholar
- 47.Wilson DB (1965) Quantitative Studies on the Behavior of Sensitized Lymphocytes in Vitro: I. Relationship of the Degree of Destruction of Homologous Target Cells to the Number of Lymphocytes and to the Time of Contact in Culture and Consideration of the Effects of Isoimmune Serum. J Exp Med 122:143–166PubMedCrossRefGoogle Scholar