Effect of calcineurin inhibitors on myotoxic activity of crotoxin and Bothrops asper phospholipase A2 myotoxins in vivo and in vitro.
Previous studies have shown that calcineurin activity plays a critical role in the myotoxic activity induced by crotoxin (CTX), a group II phospholipase A(2) (PLA(2)) with neurotoxic and myotoxic actions. In order to address whether calcineurin is also important for the activity of non-neurotoxic group II PLA(2) myotoxins we have compared the effects of calcineurin inhibition on the myotoxic capacity of CTX and the non-neurotoxic PLA(2)s, myotoxin II (Mt II) and myotoxin III (Mt III) from Bothrops asper venom. Rats were treated with cyclosporin A (CsA) or FK506, calcineurin inhibitors, and received an intramuscular injection of either CTX, Mt II or Mt III into the tibialis anterior. Animals were killed 24 h after injection of toxins. Tibialis anterior was removed and stored in liquid nitrogen. Myofibers in culture were also treated with CsA or FK506 and exposed to CTX, Mt II and Mt III. It was observed that, in contrast to CTX, CsA and FK506 do not attenuate myotoxic effects induced by both Mt II and Mt III in vivo and in vitro. The results of the present study suggest that calcineurin is not essential for the myotoxic activity of Mt II and Mt III, indicating that distinct intracellular pathways might be involved in myonecrosis induced by neurotoxic CTX and non-neurotoxic Bothrops sp. PLA(2) myotoxins. Alternatively, calcineurin dependent fast fiber type shift might render the muscle resistant to the action of CTX, without affecting its susceptibility to Bothrops sp. myotoxins.
Miyabara
E H
EH
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, Av Lineu Prestes 1524, São Paulo, 05508-900, SP, Brazil.
Baptista
I L
IL
Lomonte
B
B
Selistre-de-Araújo
H S
HS
Gutiérrez
J M
JM
Moriscot
A S
AS
D000818:Animals; D017837:Bothrops; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D017839:Crotalus; D003439:Crotoxin / Q000633:toxicity*; D016572:Cyclosporine / Q000494:pharmacology; D054501:Group II Phospholipases A2; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D010741:Phospholipases A / Q000633:toxicity; D054467:Phospholipases A2; D051381:Rats; D017208:Rats, Wistar; D030162:Reptilian Proteins; D016559:Tacrolimus / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D030162:Reptilian Proteins; D016572:Cyclosporine; D003439:Crotoxin; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; C061056:myotoxin II, Bothrops asper; C080300:myotoxin III, Bothrops asper; D016559:Tacrolimus