title: Impact of 5-lipoxygenase inhibitors on the spatiotemporal distribution of inflammatory cells and neuronal COX-2 expression following experimental traumatic brain injury in rats.
abstract: The inflammatory response following traumatic brain injury (TBI) contributes to neuronal death with poor outcome. Although anti-inflammatory strategies were beneficial in the experimental TBI, clinical translations mostly failed, probably caused by the complexity of involved cells and mediators. We recently showed in a rat model of controlled cortical impact (CCI) that leukotriene inhibitors (LIs) attenuate contusion growth and improve neuronal survival. This study focuses on spatiotemporal characteristics of macrophages and granulocytes, typically involved in inflammatory processes, and neuronal COX-2 expression. Effects of treatment with LIs (Boscari/MK-886), started prior trauma, were evaluated by quantifying CD68(+), CD43(+) and COX-2(+) cells 24h and 72 h post-CCI in the parietal cortex (PC), CA3 region, dentate gyrus (DG) and visual/auditory cortex (v/aC). Correlations were applied to identify intercellular relationships. At 24h, untreated animals showed granulocyte invasion in all regions, decreasing towards 72 h. Macrophages increased from 24h to 72 h post-CCI in PC and v/aC. COX-2(+) neurones showed no temporal changes, except of an increase in the CA3 region at 72 h. Treatment reduced granulocytes at 24h in the pericontusional zone and hippocampus, and macrophages at 72 h in the PC and v/aC. COX-2 expression remained unaffected by LIs, except of time-specific changes in the DG (increase/decrease at 24/72 h). Interrelations confirmed concomitant cellular reactions beyond the initial trauma site. In conclusion, LIs attenuated the cellular inflammatory response following CCI. Future studies have to clarify region-specific effects and explore the potential of a clinically more relevant therapeutic approach applying LIs after CCI.
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Jahnallee 59, 04109 Leipzig, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Härtig
authors.affiliation: Department of Neurology, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany. Electronic address: dominik.michalski@medizin.uni-leipzig.de.
authors.forename: Dominik
authors.initials: D
authors.lastname: Michalski
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Jahnallee 59, 04109 Leipzig, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Seeger
authors.affiliation: Department of Neurosurgery, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Voigt
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig-Site, Permoserstr. 15, 04318 Leipzig, Germany.
authors.forename: Cornelius K
authors.initials: CK
authors.lastname: Donat
authors.affiliation: Department of Neurosurgery, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Dulin
authors.affiliation: Institute of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 43, 04103 Leipzig, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kacza
authors.affiliation: Department of Neurosurgery, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Meixensberger
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Jahnallee 59, 04109 Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arendt
authors.affiliation: Department of Neurosurgery, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany; Department of Neurosurgery, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.
authors.forename: Martin U
authors.initials: MU
authors.lastname: Schuhmann
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D007211:Indoles / Q000494:pharmacology*; D051917:Leukosialin / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D018613:Microscopy, Confocal; D015213:Neuroimmunomodulation / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D000097382:CD68 Molecule; D002722:Chlorobenzenes
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D007211:Indoles; D051917:Leukosialin; D016859:Lipoxygenase Inhibitors; D018696:Neuroprotective Agents; D010936:Plant Extracts; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C060893:MK-886; D002722:Chlorobenzenes; C489691:Ptgs2 protein, rat