A study of zinc-dependent metalloendopeptidase inhibitors as pharmacological antagonists in botulinum neurotoxin poisoning.

Abstract

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.

• Authors: S S Deshpande, R E Sheridan, M Adler
• Journal: Toxicon : official journal of the International Society on Toxinology (Toxicon) Vol. 33 Issue 4 Pg. 551-7 (Apr 1995) ISSN: 0041-0101 [Print] England
• PMID: 7570640 (Publication Type: Journal Article)

Chemical References

• Glycopeptides
• Neurotoxins
• Protease Inhibitors
• Captopril
• Metalloendopeptidases
• Botulinum Toxins
• Zinc
• phosphoramidon

Topics

• Amino Acid Sequence
• Animals
• Botulinum Toxins (antagonists & inhibitors, toxicity)
• Captopril (pharmacology)
• Diaphragm (drug effects)
• Glycopeptides (pharmacology)
• In Vitro Techniques
• Male
• Metalloendopeptidases (antagonists & inhibitors)
• Mice
• Molecular Sequence Data
• Neurotoxins (antagonists & inhibitors, toxicity)
• Phrenic Nerve (drug effects)
• Protease Inhibitors (pharmacology)
• Respiratory Paralysis (chemically induced, prevention & control)
• Zinc (pharmacology)