Attenuation of ischemia/reperfusion induced MAP kinases by N-acetyl cysteine, sodium nitroprusside and phosphoramidon.
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.
Mehta
A
A
Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
Sekhon
C P S
CP
Giri
S
S
Orak
J K
JK
Singh
A K
AK
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D006020:Glycopeptides / Q000494:pharmacology*; D007150:Immunohistochemistry; D007511:Ischemia / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control; D019194:Ischemic Preconditioning; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion / Q000009:adverse effects; D015427:Reperfusion Injury / Q000201:enzymology* / Q000378:metabolism / Q000517:prevention & control*; D015996:Survival Rate; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000032:analysis; D000099169:Fos-Related Antigen 1
D000111:Acetylcysteine; D006020:Glycopeptides; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009599:Nitroprusside; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C008890:phosphoramidon