Attenuation of ischemia/reperfusion induced MAP kinases by N-acetyl cysteine, sodium nitroprusside and phosphoramidon.

Abstract

Ischemia followed by reperfusion has a number of clinically significant consequences. A number of pathophysiological processes appear to be involved in ischemia/reperfusion (I/R) injury. The mitogen activated protein kinases (MAPK) are integral components of the parallel MAP kinase cascades activated in response to a variety of cellular stress inducing ischemia/ATP depletion and inflammatory cytokines. Many studies suggest that members of the MAP kinase family in particular Jun N-terminal kinase (JNK) are activated in kidney following ischemia/reperfusion of this tissue. The present study underlines the therapeutic potential of the combination of N-acetyl cysteine (NAC), a potent antioxidant, sodium nitroprusside (SNP), a nitric oxide donor and phosphoramidon (P), an endothelin-1 converting enzyme inhibitor in ameliorating the MAPK induced damage during renal ischemia/reperfusion injury. Our previous results showed that 90 min of ischemia followed by reperfusion caused very severe injury and that the untreated animals had 100% mortality after the 3rd day whereas there was improved renal function and 100% survival of animals in the three drug combination treatment group. The present study, mainly on tissue sections, further supports the protection provided by the triple drug therapy. A higher degree of expression of all the three classes of MAPK, i.e. JNK, P38 MAP kinases and P-extracellular signal regulated kinases (ERKs) can be seen in kidneys subjected to ischemia/reperfusion insult. Pretreatment with a combination of N-acetyl cysteine, sodium nitroprusside, and phosphoramidon completely inhibits all three classes of MAPK and ameliorates AP-1 whereas individual or a combination of any two drugs is not as effective.

• Authors: A Mehta, C P S Sekhon, S Giri, J K Orak, A K Singh
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 240 Issue 1-2 Pg. 19-29 (Nov 2002) ISSN: 0300-8177 [Print] Netherlands
• PMID: 12487368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Glycopeptides
• Proto-Oncogene Proteins c-fos
• Proto-Oncogene Proteins c-jun
• Transcription Factor AP-1
• fos-related antigen 1
• Nitroprusside
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• phosphoramidon
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Disease Models, Animal
• Glycopeptides (pharmacology)
• Immunohistochemistry
• Ischemia (enzymology, metabolism, prevention & control)
• Ischemic Preconditioning
• JNK Mitogen-Activated Protein Kinases
• Male
• Mitogen-Activated Protein Kinases (metabolism)
• Nitroprusside (pharmacology)
• Phosphorylation
• Proto-Oncogene Proteins c-fos (analysis)
• Proto-Oncogene Proteins c-jun (analysis)
• Rats
• Rats, Sprague-Dawley
• Reperfusion (adverse effects)
• Reperfusion Injury (enzymology, metabolism, prevention & control)
• Survival Rate
• Time Factors
• Transcription Factor AP-1 (analysis)