Chelation of zinc antagonizes the neuromuscular blocking properties of the seven serotypes of botulinum neurotoxin as well as tetanus toxin.
Botulinum neurotoxin types A, B (unactivated and activated), C, D, E, F and G, as well as tetanus toxin, paralyzed transmission in mouse phrenic nerve-hemidiaphragm preparations. Toxin-induced blockade of transmission was antagonized by chelators [e.g., ethylenediamine tetraacetic acid, tetrakis(2-pyridylmethyl)ethylenediamine or diethylene-triaminepentaacetic anhydride], but this effect was dependent on incubation conditions. Pretreatment of toxin with chelators failed to produce antagonism, but pretreatment of tissues did produce antagonism. Of the various chelators tested, tetrakis(2-pyridylmethyl)ethylenediamine produced the greatest effect. Antagonism of toxin-induced neuromuscular blockade could be partially reversed by washing chelators from tissues and could be fully reversed by adding an excess of zinc. The ability of chelators to antagonize clostridial neurotoxins was specific and did not extend to phospholipase A2 neurotoxins. Ligand-binding studies with radioiodinated toxin and brain membrane preparations showed that chelators did not antagonize toxicity by inhibiting toxin association with receptors. Similarly, pharmacological experiments with unlabeled toxin- and type-specific antibodies demonstrated that chelators did not act by blocking receptor-mediated internalization of toxin. The chelators appeared to exert their effects by antagonizing the intracellular actions of clostridial neurotoxins. Electrophysiological studies showed that chelators, at concentrations relevant to antagonism of botulinum neurotoxin and tetanus toxin, did not enhance transmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)
Simpson
L L
LL
Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania.
Coffield
J A
JA
Bakry
N
N
D000818:Animals; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002614:Chelating Agents / Q000378:metabolism / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D009466:Neuromuscular Blocking Agents / Q000037:antagonists & inhibitors*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012680:Sensitivity and Specificity; D012703:Serotyping; D013744:Tetanus Toxin / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
D002614:Chelating Agents; D009466:Neuromuscular Blocking Agents; D013744:Tetanus Toxin; D008666:Metalloendopeptidases; D001905:Botulinum Toxins; D015032:Zinc