Kuncl R W, Drachman D B, Adams R, Lehar M
Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, Maryland 21287-7519.
J Pharmacol Exp Ther. 1993 Nov;267(2):582-9.
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.
重症肌无力的基本异常是神经肌肉接头处乙酰胆碱受体（AChRs）的耗竭，这部分归因于致病性抗体作用导致的过度内吞作用。我们研究了磷脂甲基化抑制剂3 - 脱氮腺苷（3DZA）是否能降低肌肉AChRs的内吞速率，从而干扰这一病理过程。使用3DZA的理论依据是磷脂甲基化会改变膜的性质，并且已知抑制甲基转移酶反应会减缓内吞过程。在本研究中，我们利用原代大鼠骨骼肌培养物和人类重症肌无力患者的血清，在重症肌无力的体外模型中测试了3DZA和其他甲基化抑制剂对AChRs降解和合成的影响。在正常培养物（无重症肌无力血清）中，3DZA以广泛的剂量反应关系抑制AChR降解，低至2 microM时即开始起效（P <.0001）。对AChRs的合成或肌肉细胞完整性的其他指标没有急性影响。当向培养物中加入人类重症肌无力血清以加速AChRs的内吞和降解时，3DZA仍然有力地抑制了降解速率。由于该药物通过减少内吞降解使AChRs在肌肉细胞表面膜中积累，它为人类重症肌无力的治疗提供了一种潜在策略。
