Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia-reperfusion injury in a nuclear factor-kappaB-independent manner.

Abstract

Nuclear factor kappa-B (NF-kappaB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-kappaB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-alpha expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-alpha as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-alpha but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-alpha, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-kappaB independent manner. These findings should contribute to better understand testicular torsion-induced damage.

• Authors: Letteria Minutoli, Pietro Antonuccio, Francesca Polito, Alessandra Bitto, Francesco Squadrito, Vincenzo Di Stefano, Piero Antonio Nicotina, Carmine Fazzari, Daniele Maisano, Carmelo Romeo, Domenica Altavilla
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 604 Issue 1-3 Pg. 27-35 (Feb 14 2009) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19135439 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Flavonoids
• NF-kappa B
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Apoptosis
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• Male
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, biosynthesis)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, biosynthesis)
• NF-kappa B (genetics, metabolism)
• Reperfusion Injury (enzymology, metabolism, pathology)
• Testis (blood supply, enzymology, metabolism, pathology)