title: Lipid peroxidation activates mitogen-activated protein kinases in testicular ischemia-reperfusion injury.
abstract: OBJECTIVE
  Testicular damage after torsion has been attributed to many mechanisms, of which one is lipid peroxidation of the plasma membrane, which could cause the activation of the mitogen-activated protein kinase family. These proteins are of vital importance for signal transduction pathways and 2 of them, extracellular signal-regulated kinase and c-jun N-terminal kinase, participate in the pathogenesis of testicular ischemia. We investigated whether lipid peroxidation may trigger mitogen-activated protein kinase activation in testicular ischemia-reperfusion.
  
  
  METHODS
  Adult male Sprague-Dawley rats were subjected to 1-hour testicular ischemia, followed by 24 hours of reperfusion. Sham testicular ischemia-reperfusion rats served as controls. Animals were randomized to receive raxofelast, an inhibitor of lipid peroxidation (20 mg/kg intraperitoneally administered 15 minutes before detorsion and 15 minutes after detorsion) or vehicle (1 ml/kg 10% dimethyl sulfoxide/NaCl solution). A group of animals was sacrificed 0, 10, 15, 20, 25 and 30 minutes, and 1, 2 and 3 hours, respectively, after detorsion to evaluate testicular c-jun N-terminal kinase, extracellular signal-regulated kinase and tumor necrosis factor-alpha activation by Western blot analysis, and mRNA expression and conjugated dienes using a spectrophotometer technique. Another group was sacrificed 24 hours after detorsion to evaluate histological alterations.
  
  
  RESULTS
  Testicular ischemia-reperfusion injury caused a significant increase in the conjugated diene levels, extracellular signal-regulated kinase c-jun N-terminal kinase activity and tumor necrosis factor-alpha expression in both testes. Furthermore, histological examination revealed marked damage. Raxofelast inhibited these parameters and decreased histological damage.
  
  
  CONCLUSIONS
  These data suggest that lipid peroxidation triggers extracellular signal-regulated kinase and c-jun N-terminal kinase activation. Furthermore, mitogen-activated protein kinase blockade might represent a potential therapeutic approach to treatment in patients with unilateral testicular torsion.
authors.affiliation: Department of Medical, University of Messina, Messina, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Antonuccio
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Carmelo
authors.initials: C
authors.lastname: Romeo
authors.forename: Piero Antonio
authors.initials: PA
authors.lastname: Nicòtina
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Salvatore
authors.initials: S
authors.lastname: Arena
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
authors.forename: Biagio
authors.initials: B
authors.lastname: Zuccarello
authors.forename: Francesca
authors.initials: F
authors.lastname: Polito
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D013086:Spermatic Cord Torsion / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D001572:Benzofurans; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014810:Vitamin E; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C071049:Raxofelast