title: Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody.
abstract: In myasthenia gravis, the neuromuscular junction is impaired by the antibody-mediated loss of postsynaptic acetylcholine receptors (AChRs). Muscle weakness can be improved upon treatment with pyridostigmine, a cholinesterase inhibitor, or with 3,4-diaminopyridine, which increases the release of ACh quanta. The clinical efficacy of pyridostigmine is in doubt for certain forms of myasthenia. Here we formally examined the effects of these compounds in the antibody-induced mouse model of anti-muscle-specific kinase (MuSK) myasthenia gravis. Mice received 14 daily injections of IgG from patients with anti-MuSK myasthenia gravis. This caused reductions in postsynaptic AChR densities and in endplate potential amplitudes. Systemic delivery of pyridostigmine at therapeutically relevant levels from days 7 to 14 exacerbated the anti-MuSK-induced structural alterations and functional impairment at motor endplates in the diaphragm muscle. No such effect of pyridostigmine was found in mice receiving control human IgG. Mice receiving smaller amounts of MuSK autoantibodies did not display overt weakness, but 9 days of pyridostigmine treatment precipitated generalised muscle weakness. In contrast, one week of treatment with 3,4-diaminopyridine enhanced neuromuscular transmission in the diaphragm muscle. Both pyridostigmine and 3,4-diaminopyridine increase ACh in the synaptic cleft yet only pyridostigmine potentiated the anti-MuSK-induced decline in endplate ACh receptor density. These results thus suggest that ongoing pyridostigmine treatment potentiates anti-MuSK-induced AChR loss by prolonging the activity of ACh in the synaptic cleft.
authors: School of Medical Sciences (Physiology) and Bosch Institute, Anderson Stuart Bldg (F13), University of Sydney, NSW 2006, Australia.
authors: Marco
authors: M
authors: Morsch
authors: Stephen W
authors: SW
authors: Reddel
authors: Nazanin
authors: N
authors: Ghazanfari
authors: Klaus V
authors: KV
authors: Toyka
authors: William D
authors: WD
authors: Phillips
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077770:Amifampridine; D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D005071:Evoked Potentials; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018908:Muscle Weakness / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000502:physiology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D011729:Pyridostigmine Bromide / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000502:physiology*
chemical_list: D001323:Autoantibodies; D002800:Cholinesterase Inhibitors; D007074:Immunoglobulin G; D011950:Receptors, Cholinergic; D015761:4-Aminopyridine; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D011729:Pyridostigmine Bromide; D000077770:Amifampridine