A study of zinc-dependent metalloendopeptidase inhibitors as pharmacological antagonists in botulinum neurotoxin poisoning.
Zinc-dependent metalloprotease inhibitors phosphoramidon, captopril and a peptide hydroxamate were studied as potential pretreatment compounds by examining their ability to delay the onset or to prolong the time to 50% block of nerve-elicited muscle twitch tension in the mouse phrenic-nerve diaphragm (in vitro at 36 degrees C) after botulinum neurotoxin serotypes A and B (BoNT-A, BoNT-B). Addition of BoNT-A or BoNT-B (1 x 10(-10) M) produced 50% block of the twitch response at 56 +/- 9 min and 76 +/- 4 min, respectively. Preincubation (45 min) of muscles with phosphoramidon (0.2 mM) prolonged the time to 50% block by 15 min in BoNT-B-poisoned muscles with no effect on the time-course of paralysis in BoNT-A exposed muscles. When the same quantities of BoNT-A or BoNT-B (equivalent to 1 x 10(-10) M bath concentration) were preincubated for 2 hr with phosphoramidon (equivalent to 0.2 mM final bath concentration), and the incubation mixture was added to the muscle chamber, the times to 50% block were prolonged by 38 min and 18 min for BoNT-B and BoNT-A, respectively. Preincubation of diaphragms with captopril (up to 10 mM) or peptide hydroxamate (75 microM) failed to antagonize BoNT-A or BoNT-B-induced neuromuscular block. Among the three metalloprotease inhibitors examined here, only phosphoramidon showed a significant protection against both serotypes of BoNT. A search for better inhibitor compounds specifically tailored to match the active site on BoNT molecule deserves attention.
Deshpande
S S
SS
Neurotoxicology Branch, USAMRICD, Aberdeen Proving Ground, MD 21010-5425, USA.
Sheridan
R E
RE
Adler
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002216:Captopril / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects; D006020:Glycopeptides / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010791:Phrenic Nerve / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D012133:Respiratory Paralysis / Q000139:chemically induced / Q000517:prevention & control; D015032:Zinc / Q000494:pharmacology*
D006020:Glycopeptides; D009498:Neurotoxins; D011480:Protease Inhibitors; D002216:Captopril; D008666:Metalloendopeptidases; D001905:Botulinum Toxins; D015032:Zinc; C008890:phosphoramidon