Intravenous immunoglobulin (IVIg) treatment improves mus- cle strength in Lambert-Eaton myasthenic syndrome (LEMS), butits specific mod e of action is unknown. We have delineated its mode of action on neuromuscular b ...Intravenous immunoglobulin (IVIg) treatment improves mus- cle strength in Lambert-Eaton myasthenic syndrome (LEMS), butits specific mod e of action is unknown. We have delineated its mode of action on neuromuscular b locking properties of LEMS IgG. The effect of sera and purified IgG from six pat ients with LEMS on evoked quantal release was investigated after direct applicat ion to the motor nerve terminal by the perfused macro-patch-clamp electrode in mouse hemidiaphragms. The effect of LEMS IgG was analyzed alone and after coinc ubation with different concentrations of IVIg or its Fab fragments. All LEMS ser a and purified LEMS IgG fractions taken before IVIg treatment inhibited evoked q uantal release in a dose-dependent manner. When LEMS IgG was coincubated with a therapeutic IVIg preparation, presynaptic inhibitory activity of LEMS IgG was d iminished in a dose-dependent fashion. Monovalent Fab fragments were as effecti ve in neutralizing the activity of LEMS IgG as whole IVIg. These direct neutrali zing effects of IVIg may explain its therapeutic efficacy.展开更多
AIM：Toosendanin is a pre-synaptic blocer at the neuromuscular junction and its inhititory effect is divided into an initial facilitatve/stimulatory phase followed by a prolonged inhibitory phase,The present study inv...AIM：Toosendanin is a pre-synaptic blocer at the neuromuscular junction and its inhititory effect is divided into an initial facilitatve/stimulatory phase followed by a prolonged inhibitory phase,The present study investigated whether the subsequent inhibitory phase was due to exhaustion of the secretory machinery as a result of extensive stimulation during the initial facilitative phase More specifically,this paper examined whether toosendanin could directly inhibit the secretory machinery in exocrine cells.METHODS:Rat pancreatic acinar cells were isolated by collagenase digestion,Secretion was assessed by measuring the amount of amylase released into the extracellular medium as a percentage of the total present in the cells before stimulation.Cholecystokinin(CCK)-induced increases in intracellular calcium in single cells were measured with fura-2microfluorometry.RESULTS:Effects of toosendanin on CCK-induced amylase secretion and calcium oscillations were investigated.Toosendanin of 87-870μMhad no effect on 10pM-100nMCCK-stimulated amylase secretion.nor did 8.7-870μMtoosendanin inhibit 5pM CCK-induced calcium oscillations.In contrast,10nMCCK1recepto antagonistFK480completely blocked5pM CCK-induced calcium oscillations.CONCLUSION;The pre-synaptic“blocker”toosendanin is a selective activator of the voltage-dependent calcium channels but does not interfere with the secretory machinery itself.展开更多
文摘Intravenous immunoglobulin (IVIg) treatment improves mus- cle strength in Lambert-Eaton myasthenic syndrome (LEMS), butits specific mod e of action is unknown. We have delineated its mode of action on neuromuscular b locking properties of LEMS IgG. The effect of sera and purified IgG from six pat ients with LEMS on evoked quantal release was investigated after direct applicat ion to the motor nerve terminal by the perfused macro-patch-clamp electrode in mouse hemidiaphragms. The effect of LEMS IgG was analyzed alone and after coinc ubation with different concentrations of IVIg or its Fab fragments. All LEMS ser a and purified LEMS IgG fractions taken before IVIg treatment inhibited evoked q uantal release in a dose-dependent manner. When LEMS IgG was coincubated with a therapeutic IVIg preparation, presynaptic inhibitory activity of LEMS IgG was d iminished in a dose-dependent fashion. Monovalent Fab fragments were as effecti ve in neutralizing the activity of LEMS IgG as whole IVIg. These direct neutrali zing effects of IVIg may explain its therapeutic efficacy.
基金Natural Science Foundation of China Grant No.39870367,39825112,30070286The Ph.D.Program of the Ministry of Education,China.
文摘AIM：Toosendanin is a pre-synaptic blocer at the neuromuscular junction and its inhititory effect is divided into an initial facilitatve/stimulatory phase followed by a prolonged inhibitory phase,The present study investigated whether the subsequent inhibitory phase was due to exhaustion of the secretory machinery as a result of extensive stimulation during the initial facilitative phase More specifically,this paper examined whether toosendanin could directly inhibit the secretory machinery in exocrine cells.METHODS:Rat pancreatic acinar cells were isolated by collagenase digestion,Secretion was assessed by measuring the amount of amylase released into the extracellular medium as a percentage of the total present in the cells before stimulation.Cholecystokinin(CCK)-induced increases in intracellular calcium in single cells were measured with fura-2microfluorometry.RESULTS:Effects of toosendanin on CCK-induced amylase secretion and calcium oscillations were investigated.Toosendanin of 87-870μMhad no effect on 10pM-100nMCCK-stimulated amylase secretion.nor did 8.7-870μMtoosendanin inhibit 5pM CCK-induced calcium oscillations.In contrast,10nMCCK1recepto antagonistFK480completely blocked5pM CCK-induced calcium oscillations.CONCLUSION;The pre-synaptic“blocker”toosendanin is a selective activator of the voltage-dependent calcium channels but does not interfere with the secretory machinery itself.
