title: Peroxisome proliferator activated receptor beta/delta activation prevents extracellular regulated kinase 1/2 phosphorylation and protects the testis from ischemia and reperfusion injury.
abstract: OBJECTIVE
  Testicular torsion is a medical emergency that requires immediate diagnosis and treatment to avoid subsequent testicular injury and infertility. PPARs are a family of nuclear hormone receptors belonging to the steroid receptor superfamily. Three PPAR isotypes (alpha, beta/delta and gamma) encoded by separate genes and showing different tissue distribution patterns have been identified. PPARbeta/delta is expressed in testis and its role is largely unknown. We tested whether pharmacological activation of PPARbeta/delta might protect the testis from ischemia and reperfusion injury.
  
  
  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. The animals were randomized to receive immediately after detorsion 1) L-165,041 (4 mg/kg intraperitoneally), a potent agonist of PPARbeta/delta, 2) GW9662 (Calbiochem(R)) (4 mg/kg intraperitoneally), an antagonist of PPAR, 3) L-165,041 (4 mg/kg intraperitoneally) plus GW9662 (4 mg/kg intraperitoneally) concomitantly or 4) vehicle (1 ml/kg 10% dimethyl sulfoxide/NaCl solution). We evaluated testicular extracellular signal regulated kinase, tumor necrosis factor-alpha and interleukin-6 by Western blot. We also investigated PPARbeta/delta activation by Western blot, mRNA expression and organ damage.
  
  
  RESULTS
  Testicular ischemia-reperfusion injury caused a significant increase in extracellular signal regulated kinase, tumor necrosis factor-alpha and interleukin-6 expression in each testis. Furthermore, histological examination revealed marked damage. L-165,041 administration increased the PPARbeta/delta message and protein, inhibited extracellular signal regulated kinase, tumor necrosis factor-alpha and interleukin-6 expression, and decreased histological damage. Concomitant administration of GW9662 reversed the protection exerted by PPARbeta/delta agonist.
  
  
  CONCLUSIONS
  These findings indicate that PPARbeta/delta agonists might be an attractive therapeutic candidate for managing testicular torsion.
authors.affiliation: Departments of Clinical and Experimental Medicine and Pharmacology (Section of Pharmacology), University of Messina, Messina, Italy.
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Pietro
authors.initials: P
authors.lastname: Antonuccio
authors.forename: Francesca
authors.initials: F
authors.lastname: Polito
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.forename: Piero Antonio
authors.initials: PA
authors.lastname: Nicotina
authors.forename: Carmine
authors.initials: C
authors.lastname: Fazzari
authors.forename: Angela Simona
authors.initials: AS
authors.lastname: Montalto
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Stefano
authors.forename: Carmelo
authors.initials: C
authors.lastname: Romeo
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
mesh_terms: D000818:Animals; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D047493:PPAR alpha / Q000502:physiology*; D047494:PPAR delta / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D013737:Testis / Q000098:blood supply*
chemical_list: D047493:PPAR alpha; D047494:PPAR delta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3