Peroxisome proliferator activated receptor beta/delta activation prevents extracellular regulated kinase 1/2 phosphorylation and protects the testis from ischemia and reperfusion injury.
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.
Minutoli
Letteria
L
Departments of Clinical and Experimental Medicine and Pharmacology (Section of Pharmacology), University of Messina, Messina, Italy.
Antonuccio
Pietro
P
Polito
Francesca
F
Bitto
Alessandra
A
Squadrito
Francesco
F
Irrera
Natasha
N
Nicotina
Piero Antonio
PA
Fazzari
Carmine
C
Montalto
Angela Simona
AS
Di Stefano
Vincenzo
V
Romeo
Carmelo
C
Altavilla
Domenica
D
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*
D047493:PPAR alpha; D047494:PPAR delta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3