Suramin inhibits the toxic effects of presynaptic neurotoxins at the mouse motor nerve terminals.
Clinically available chemical antagonists of snake neurotoxins still await to be identified. In this study, we demonstrate that an anti-trypanosomiasis agent, suramin, is an effective inhibitor of beta-bungarotoxin isolated from the venom of Formosan Krait snake. Following intraperitoneal injection (12 ng/g) of beta-bungarotoxin in mice, the time to paralysis (loss a limb withdrawal reflex, 21. 8+/-3.4 h, n=4) was significantly prolonged after intravenous injection (16 microg/g) of suramin (35.9+/-4.0 h, n=4, P<0.05). The mechanism of this inhibitory effect of suramin was analyzed at the mouse nerve terminals. beta-Bungarotoxin (1 microg/ml) produces an irreversible blocking effect of nerve-evoked muscle contractions of mouse phrenic nerve-diaphragm (blocking time 135+/-6 min, n=6). Pretreatment with suramin (0.3 mM) significantly prolonged the blocking time by three-fold. This selective inhibitory effect of suramin was further confirmed when suramin was shown to delay the neuromuscular blocking effect of another presynaptic neurotoxin, crotoxin (from American rattlesnake venom), but not that of the postsynaptic neurotoxin, alpha-bungarotoxin. Furthermore, suramin inhibited beta-bungarotoxin in blocking transmitter release as revealed by prolonging the time to abolish the end-plate potential amplitude (with suramin, 391+/-8 min; without treatment, 141+/-5 min). K(+) current was measured in the mouse triangularis sterni preparation; suramin (0.3 mM) had no significant effect on beta-bungarotoxin in inhibiting K(+) current (77+/-3% of control; with suramin 75+/-3% of control, respectively). These findings clearly show that suramin is an inhibitor of presynaptic neurotoxins, mediated by interrupting the toxins in blocking the releasing mechanism of transmitter at the motor nerve terminals. The implication of these findings is that suramin and related compounds can become useful agents in management of snakebites.
Lin-Shiau
S Y
SY
Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Sec 1, Jen-Ai Road, Taipei, Taiwan.
Lin
M J
MJ
D000818:Animals; D002038:Bungarotoxins / Q000633:toxicity*; D003964:Diaphragm / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D005071:Evoked Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D019148:Neuromuscular Blockade; D010243:Paralysis / Q000139:chemically induced / Q000517:prevention & control; D010791:Phrenic Nerve / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000502:physiology; D013498:Suramin / Q000494:pharmacology*; D013997:Time Factors
D002038:Bungarotoxins; D015221:Potassium Channels; D013498:Suramin