title: COX-2 regulation and TUNEL-positive cell death differ between genders in the secondary inflammatory response following experimental penetrating focal brain injury in rats.
abstract: BACKGROUND
  Traumatic brain injury is followed by secondary neuronal degeneration, largely dependent on an inflammatory response. This response is probably gender specific, since females are better protected than males in experimental models. The reasons are not fully known. We examined aspects of the inflammatory response following experimental TBI in male and female rats to explore possible gender differences at 24 h and 72 h after trauma, times of peak histological inflammation and neuronal degeneration.
  
  
  METHODS
  A penetrating brain injury model was used to produce penetrating focal TBI in 20 Sprague-Dawley rats, 5 males and 5 females for each time point. After 24 and 72 h the brains were removed and subjected to in situ hybridization and immunohistochemical analyses for COX-2, iNOS, osteopontin, glial fibrillary acidic protein, 3-nitrotyrosine, TUNEL and Fluoro-Jade.
  
  
  RESULTS
  COX-2 mRNA and protein levels were increased in the perilesional area compared to the uninjured contralateral side and significantly higher in males at 24 h and 72 h (p < 0.05). iNOS mRNA was significantly increased in females at 24 h (p < 0.05) although protein was not. TUNEL was increased in male rats after 24 h (p < 0.05). Glial fibrillary acidic protein, osteopontin, 3-nitrotyrosine and Fluoro-Jade stained degenerating neurons were increased in the perilesional area, showing no difference between genders.
  
  
  CONCLUSIONS
  COX-2 regulation differed between genders after TBI. The increased COX-2 expression in male rats correlated with increased apoptotic cell death detected by increased TUNEL staining at 24 h, but not with neuronal necrosis measured by Flouro-Jade. Astrogliosis and microgliosis did not differ, confirming a comparable level of trauma. The gender-specific trait of the secondary inflammatory response may be connected to prostaglandin regulation, which may partially explain gender variances in outcome after TBI.
authors.affiliation: Department of Neuroscience, Experimental Traumatology Unit, Karolinska Institutet, Stockholm, Sweden, mattias.gunther@ki.se.
authors.forename: Mattias
authors.initials: M
authors.lastname: Günther
authors.forename: Stefan
authors.initials: S
authors.lastname: Plantman
authors.forename: Johan
authors.initials: J
authors.lastname: Davidsson
authors.forename: Maria
authors.initials: M
authors.lastname: Angéria
authors.forename: Tiit
authors.initials: T
authors.lastname: Mathiesen
authors.forename: Mårten
authors.initials: M
authors.lastname: Risling
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020197:Head Injuries, Penetrating / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
chemical_list: D005904:Glial Fibrillary Acidic Protein; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2