title: Neuronal degeneration and iNOS expression in experimental brain contusion following treatment with colchicine, dexamethasone, tirilazad mesylate and nimodipine.
abstract: BACKGROUND
  The pathophysiological mechanisms of secondary neurological injury after traumatic brain injury are complex. Post-traumatic biochemical reactions include parenchymal inflammation, free radical production, increased intracellular calcium and lipid peroxidation and nitric oxide production. The relative importance of each mechanism is unknown in brain contusions. This study was undertaken to investigate protection by the neuroprotective and/or anti-inflammatory drugs that have different putative mechanisms of action: colchicine, dexamethasone, tirilazad mesylate and nimodipine.
  
  
  METHODS
  A brain contusion was produced using a weight-drop model in rats. The animals were treated with either one of the drugs at previously defined relevant dosage or control. Fluoro-Jade labelling, TUNEL-staining and immunohisto-chemistry were used to study neuronal degeneration, cellular apoptosis and iNOS expression. In addition, the number of surviving neurons after 14 days was determined.
  
  
  RESULTS
  The number of degenerating neurons was significantly reduced in all treatment groups at 24 hours while the total number of apoptotic cells including inflammatory cells and glia was unchanged. iNOS-expression was reduced in all treatment groups at 24 hours but not later. Only colchicine and tirilazad mesylate significantly enhanced neuronal survival at 14 days after injury.
  
  
  CONCLUSIONS
  The findings underscored that an early neuroprotective effect does not necessarily lead to increased long-term neuronal survival. The absence of a significant long-term effect with nimodipine and dexamethasone agrees with clinical studies. Colchicine with an anti-macrophage/anti-inflammatory activity and the free radical scavenger tirilazad mesylate were effective for amelioration of experimental contusion with moderate energy transfer. Early neuroprotection may to some extent target iNOS via different pathways since all tested drugs affected both iNOS expression and neuronal degeneration.
authors.affiliation: Department of Clinical Neuroscience, Section of Neurosurgery, Karolinska Institute, Stockholm, Sweden. gahm@karolinska.se
authors.forename: C
authors.initials: C
authors.lastname: Gahm
authors.forename: S
authors.initials: S
authors.lastname: Holmin
authors.forename: S
authors.initials: S
authors.lastname: Rudehill
authors.forename: T
authors.initials: T
authors.lastname: Mathiesen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D001930:Brain Injuries / Q000150:complications* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003078:Colchicine / Q000494:pharmacology / Q000627:therapeutic use; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D005452:Fluoresceins; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D020287:In Situ Nick-End Labeling; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009553:Nimodipine / Q000494:pharmacology / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009930:Organic Chemicals; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011281:Pregnatrienes / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D002121:Calcium Channel Blockers; D005452:Fluoresceins; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D011281:Pregnatrienes; C435731:fluoro jade; D009569:Nitric Oxide; D009553:Nimodipine; D003907:Dexamethasone; D052247:Nitric Oxide Synthase Type II; D003078:Colchicine; C053355:tirilazad