PMID- 23440963
OWN - NLM
STAT- MEDLINE
DCOM- 20131205
LR  - 20220330
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 591
IP  - 10
DP  - 2013 May 15
TI  - Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and 
      myasthenia induced in mice by muscle-specific kinase autoantibody.
PG  - 2747-62
LID - 10.1113/jphysiol.2013.251827 [doi]
AB  - 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.
FAU - Morsch, Marco
AU  - Morsch M
AD  - School of Medical Sciences (Physiology) and Bosch Institute, Anderson Stuart Bldg 
      (F13), University of Sydney, NSW 2006, Australia.
FAU - Reddel, Stephen W
AU  - Reddel SW
FAU - Ghazanfari, Nazanin
AU  - Ghazanfari N
FAU - Toyka, Klaus V
AU  - Toyka KV
FAU - Phillips, William D
AU  - Phillips WD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130225
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 0 (Autoantibodies)
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Receptors, Cholinergic)
RN  - BH3B64OKL9 (4-Aminopyridine)
RN  - EC 2.7.10.1 (MuSK protein, mouse)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - KVI301NA53 (Pyridostigmine Bromide)
RN  - RU4S6E2G0J (Amifampridine)
SB  - IM
MH  - 4-Aminopyridine/analogs & derivatives/pharmacology
MH  - Amifampridine
MH  - Animals
MH  - Autoantibodies/pharmacology
MH  - Cholinesterase Inhibitors/pharmacology
MH  - Evoked Potentials
MH  - Female
MH  - Humans
MH  - Immunoglobulin G/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Muscle Weakness/*physiopathology
MH  - Muscle, Skeletal/physiology
MH  - Myasthenia Gravis, Autoimmune, Experimental/*physiopathology
MH  - Neuromuscular Junction/drug effects/physiology
MH  - Pyridostigmine Bromide/pharmacology
MH  - Receptor Protein-Tyrosine Kinases/*physiology
MH  - Receptors, Cholinergic/*physiology
PMC - PMC3678053
EDAT- 2013/02/27 06:00
MHDA- 2013/12/16 06:00
PMCR- 2014/05/15
CRDT- 2013/02/27 06:00
PHST- 2013/02/27 06:00 [entrez]
PHST- 2013/02/27 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2014/05/15 00:00 [pmc-release]
AID - jphysiol.2013.251827 [pii]
AID - 10.1113/jphysiol.2013.251827 [doi]
PST - ppublish
SO  - J Physiol. 2013 May 15;591(10):2747-62. doi: 10.1113/jphysiol.2013.251827. Epub 
      2013 Feb 25.