A preclinical evaluation of aminopyridines as putative therapeutic agents in the treatment of botulism

Abstract

4-Aminopyridine and 3,4-diaminopyridine were evaluated for their abilities to delay the onset of paralysis due to botulinum neurotoxin types A, B, and E. Experiments were done on phrenic nerve-hemidiaphragm preparations excised from mice. At a concentration that produced an enhancement in muscle twitch amplitude, 4-aminopyridine and 3,4-diaminopyridine delayed the onset of paralysis due to botulinum toxin type A. Under the same conditions, the drugs did little to protect tissues against botulinum toxin types B and E. 3,4-Diaminopyridine was also evaluated for its ability to reverse the paralysis due to botulinum toxin. Experiments were done on rat phrenic nerve-hemidiaphragm preparations that had previously been poisoned in vivo. The drug produced transient increases in neuromuscular transmission, with the effect being greater for botulinum neurotoxin type A than for botulinum neurotoxin types B and E. Equivalent types of experiments were done with tetanus toxin. The results with 3,4-diaminopyridine showed that tetanus toxin resembled botulinum toxin types B and E. The data help to clarify the role of aminopyridines as therapeutic agents in the treatment of botulism. They also provide insights into the mechanism of action of clostridial neurotoxins.