Onset dynamics of type A botulinum neurotoxin-induced paralysis

• DOI: 10.1007/s10928-008-9087-3
• Publication Date: 2008-06-12T18:16:24Z
• Authors: Frank J. Lebeda; Michael Adler; Keith Erickson; Yaroslav Chushak
• Keywords: Neurotoxin; Botulinum neurotoxin; Flaccid paralysis; Botulism

Experimental studies have demonstrated that botulinum neurotoxin serotype A (BoNT/A) causes flaccid paralysis by a multi-step mechanism. Following its binding to specific receptors at peripheral cholinergic nerve endings, BoNT/A is internalized receptor-mediated endocytosis. Subsequently zinc-dependent catalytic domain translocates into the neuroplasm where it cleaves vesicle-docking protein, SNAP-25, block neurally evoked neurotransmission. We tested hypothesis mathematical models having minimal number of reactions and reactants can simulate published data concerning onset skeletal muscles induced isolated rat neuromuscular junction (NMJ) in other systems. from several laboratories were simulated with two different represented sets coupled, first-order differential equations. In this study, 3-step sequential model developed Simpson (J Pharmacol Exp Ther 212:16–21,1980) was used estimate upper limits times during which anti-toxins impermeable inhibitors exert an effect. The experimentally determined reaction rate verified be consistent estimates for constants dissociating receptors. Because not designed reproduce temporal changes toxin concentrations, new species (k S ) added beginning sequence create 4-step scheme. This unbound initial transformed k free capable binding. By systematically adjusting values kS, rapid decline NMJ function ≥0.01), less mice following i.m. injections = 0.001), slow therapeutic effects < 0.001) man. modeling approach only simulating experimental results, helped quantitatively define time available inhibitor some effect (tinhib) relation between onset. predicted as becomes slower, estimated become longer. More generally, may useful studying kinetics toxins or viruses invade host cells similar mechanisms, e.g.,