4-Nitrobenzylidene malononitrile reduces apoptosis-mediated liver injury in mice.
BACKGROUND
Apoptosis plays a role in experimental and clinically related liver damage. Inhibitors of tyrosine kinases were shown to modulate apoptosis induced by different agents in various cell types.


OBJECTIVE
Investigation of the effect of 4-nitrobenzylidene malononitrile (belonging to the tyrphostins family which are selective inhibitors of protein tyrosine kinases) on apoptosis-mediated acute liver injury.


METHODS
Two murine experimental models exhibiting apoptosis-mediated liver injury were used: (1) mice treated with tumor necrosis factor-alpha and D-galactosamine; and (2) mice treated with anti-Fas antibody. Liver injury was assessed by serum levels of transaminases and by microscopic analysis. Apoptosis was assessed by labeling of apoptotic cells in the liver by the TUNEL assay and by determination of caspase-3 activity.


RESULTS
Pretreatment of mice with 4-nitrobenzylidene malononitrile reduced tumor necrosis factor-alpha/D-galactosamine-induced hepatotoxicity. TUNEL positive cells in sections from livers treated with vehicle (control), 4-nitrobenzylidene malononitrile, tumor necrosis factor-/d-galactosamine and tumor necrosis factor-alpha/D-galactosamine and 4-nitrobenzylidene malononitrile, were >0.2, >0.2, 49+/-2.3 and 4+/-0.2 per mm(2), respectively. 4-Nitrobenzylidene malononitrile also reduced hepatotoxicity induced by anti-Fas antibody. Caspase-3 activation induced by either tumor necrosis factor-alpha/D-glactosamine or by anti-Fas treatment, was reduced by pretreatment with N-nitrobenzylidene malononitrile.


CONCLUSIONS
The findings may provide a base for development of a new therapeutic modality to reduce apoptosis-mediated liver damage.
Vanichkin
Alexey
A
The Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel.
Patya
Miriam
M
Lagovsky
Irina
I
Meshorer
Asher
A
Novogrodsky
Abraham
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005688:Galactosamine / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D020287:In Situ Nick-End Labeling; D008107:Liver Diseases / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology*
C112766:4-nitrobenzylidene malononitrile; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C411023:anti-Fas monoclonal antibody; D005688:Galactosamine; D000637:Transaminases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases