EFFECT OF 3,4-DIAMINOPYRIDINE ON RAT EXTENSOR DIGITORUM LONGUS MUSCLEPARALYZED BY LOCAL INJECTION OF BOTULINUM NEUROTOXIN

The actions of the K+ channel blocker, 3,4-diaminopyridine (3,4-DAP), were studied in the rat extensor digitorum longus (EDL) muscle followi ng local inhibition of neuromuscular transmission by botulinum neuroto xin (BoNT). Local paralysis of the EDL muscle was induced by s.c. inje ctions of BoNT serotypes A, B, E or F over the anterior tibialis muscl e, One to 14 days later, the rats were anesthetized with urethane, and isometric twitch tensions following stimulation of the peroneal nerve were measured in situ. Muscles were paralyzed within 24 hr of adminis tration of 5 mouse LD(50) units (U) of BoNT/A and remained inhibited f or the entire 14-day period of observation. Similar levels of inhibiti on, but of shorter duration, were observed after local injection of 20 U of BoNT/E, 10(4) U of BoNT/B or 20 U of BoNT/F. 3,4-DAP (4 mg/kg, i .v.) potentiated twitch tensions markedly in BoNT/A intoxicated muscle . The increase in tension developed rapidly (halftime = 5.81 +/- 0.6 m in), persisted for approximately 1 hr, then decayed slowly with a half time of 25.2 +/- 4.6 min. Subsequent administration of 3,4-DAP restore d tensions to the original maxima, and this procedure could be repeate d up to eight times with no decrement. The action of 3,4-DAP was compa rable when given 1, 2, 3 or 7 days after BoNT/A and enhanced when admi nistered 14 days after toxin injection. 3,4-DAP was less effective in reversing BoNT/E-induced muscle paralysis and nearly ineffective in an tagonizing the paralytic actions of BoNT/B or BoNT/F. The results indi cate that 3,4-DAP is of benefit in BoNT/A and BoNT/E intoxication, but is of marginal value after exposure to serotypes B and F.