3-Deazaadenosine: a therapeutic strategy for myasthenia gravis by decreasing the endocytosis of acetylcholine receptors.
The basic abnormality in myasthenia gravis is the depletion of acetylcholine receptors (AChRs) at neuromuscular junctions, which is due in part to excessive endocytosis brought about by the action of pathogenic antibodies. We asked whether 3-deazaadenosine (3DZA), an inhibitor of phospholipid methylation, could decrease the rate of endocytosis of muscle AChRs and thereby interfere with this pathological process. The rationale for the use of 3DZA is that methylation of phospholipids alters membrane properties, and inhibition of methyltransferase reactions is known to slow the process of endocytosis. In this study, we have tested the effects of 3DZA and other methylation inhibitors on the degradation and synthesis of AChRs in an in vitro model of myasthenia gravis, using primary rat skeletal muscle cultures and serum from human myasthenic patients. In normal cultures (without myasthenic serum), 3DZA inhibited AChR degradation with a broad dose-response relationship, beginning as low as 2 microM (P < .0001). There was no acute effect on synthesis of AChRs or on other measures of muscle cell integrity. When human myasthenic serum was added to the cultures to accelerate the endocytosis and degradation of AChRs, 3DZA still potently inhibited the degradation rate. Because the drug allows accumulation of AChRs in the surface membrane of the muscle cell by reducing endocytotic degradation, it provides a potential strategy for therapy in human myasthenia gravis.
Kuncl
R W
RW
Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, Maryland 21287-7519.
Drachman
D B
DB
Adams
R
R
Lehar
M
M
D000818:Animals; D002478:Cells, Cultured; D003864:Depression, Chemical; D004705:Endocytosis / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D008745:Methylation; D009124:Muscle Proteins / Q000096:biosynthesis; D009132:Muscles / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009157:Myasthenia Gravis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D011950:Receptors, Cholinergic / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D014372:Tubercidin / Q000494:pharmacology*
D009124:Muscle Proteins; D011950:Receptors, Cholinergic; C018258:3-deazaadenosine; D014372:Tubercidin