Lipid peroxidation activates mitogen-activated protein kinases in testicular ischemia-reperfusion injury.
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.
Antonuccio
Pietro
P
Department of Medical, University of Messina, Messina, Italy.
Minutoli
Letteria
L
Romeo
Carmelo
C
Nicòtina
Piero Antonio
PA
Bitto
Alessandra
A
Arena
Salvatore
S
Altavilla
Domenica
D
Zuccarello
Biagio
B
Polito
Francesca
F
Squadrito
Francesco
F
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
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