Efficacy of certain quinolines as pharmacological antagonists in botulinum neurotoxin poisoning.
Various 4- and 8-aminoquinolines, which are effective antimalarial agents, were examined as potential pretreatment compounds for prolongation of the time to 50% block of nerve-elicited muscle twitches in isolated mouse diaphragms exposed to botulinum type A neurotoxin. The 4-aminoquinolines (chloroquine, amodiaquine) and quinacrine, an acridine derivative similar to chloroquine, prolonged the time required for botulinum type A neurotoxin to block neuromuscular transmission by more than 3-fold; 8-aminoquinolines (primaquine and WR242511) had no antibotulinum type A neurotoxin activity. Pyrimethamine, an antimalarial drug lacking the quinoline ring structure, was also ineffective. Rank order potencies based on equimolar effective concentrations for the test compounds were quinacrine > amodiaquine > chloroquine > quinine or quinidine. Maximum protection from botulinum type A neurotoxin-induced neuromuscular block was achieved when muscles were exposed to drug prior to or simultaneously with the toxin. A delay of more than 20 min abolished the protective ability of the antimalarial agents, presumably owing to the release of the toxin from endosomes in quantities sufficient to initiate neuromuscular block. All of the test compounds except quinine and quinidine depressed muscle contractions when concentrations exceeded 20 microM. In addition, amodiaquine at 50 microM induced muscle contracture. A combination of agents at low concentrations that act at different steps of botulinum type A neurotoxin poisoning potentiated the prolongation of time to 50% block in an approximately additive fashion. Thus N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (2 microM) and quinacrine (5 microM), when administered in combination, produced up to a 4-fold increase in time to 50% block. A similar level of protection with quinacrine alone required a 4-fold increase in the aminoquinoline concentration. Although the mechanism of protection by these antimalarial agents is probably through the raising of endosomal pH, the possibility that some of these drugs could also act by inhibiting toxin-induced channel formation cannot be ruled out.
Deshpande
S S
SS
Neurotoxicology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
Sheridan
R E
RE
Adler
M
M
D000634:Aminoquinolines / Q000627:therapeutic use*; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D009128:Muscle Spasticity / Q000139:chemically induced / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D000962:Antimalarials; D019274:Botulinum Toxins, Type A