Laschet J, Guillaume D, Grisar T, Vergniolle-Burette M, Minet A
Laboratory of Biochemistry, University of Liège, Belgium.
Epilepsia. 1991 Jan-Feb;32(1):151-6. doi: 10.1111/j.1528-1157.1991.tb05628.x.
Milacemide (MLM, CP 1552 S, 2-N-pentylaminoacetamide), a glycinamide derivative, is currently being evaluated clinically for antiepileptic activity. Anticonvulsant properties have been shown in various animal models, but the mechanism of action of MLM is unclear. We studied its activity in audiogenic seizures of DBA/2J mice. MLM was effective in inhibiting the convulsions induced by sound with a biphasic dose-effect relation. The ED50 was 109 mg/kg orally against tonic extension. Higher doses were necessary to abolish clonic convulsion and running response. Because impaired cerebral (Na+, K+)-ATPase activity is supposed to play a role in epileptogenesis, we tested MLM on in vitro cortical enzymatic activity of DBA/2J mice. Basal (Na+, K+)-ATPase activity was unchanged by several concentrations of MLM in normal C57BL/6J and audiogenic DBA/2J mice. K+ activation (from 3 to 18 mM) of (Na+, K+)-ATPase is abolished in DBA/2J mice as compared with C57BL/6J mice, suggesting impaired glial (Na+, K+)-ATPase. In the presence of MLM (from 30 to 1000 mg/L), cortical (Na+, K+)-ATPase of DBA/2J mice is activated by high concentrations of K+, as in C57BL/6J mice. Results suggest that the antiepileptic activity of MLM in audiogenic mice may be secondary to an activation of a deficient glial (Na+, K+)-ATPase.
米拉美胺（MLM，CP 1552 S，2 - N - 戊基氨基乙酰胺），一种甘氨酰胺衍生物，目前正在进行抗癫痫活性的临床评估。在各种动物模型中已显示出其抗惊厥特性，但MLM的作用机制尚不清楚。我们研究了其在DBA/2J小鼠听源性惊厥中的活性。MLM能有效抑制声音诱发的惊厥，呈现双相剂量 - 效应关系。口服时，其对强直性伸展的半数有效量（ED50）为109 mg/kg。需要更高剂量才能消除阵挛性惊厥和奔跑反应。由于脑（Na⁺，K⁺）-ATP酶活性受损被认为在癫痫发生中起作用，我们检测了MLM对DBA/2J小鼠体外皮质酶活性的影响。在正常C57BL/6J小鼠和听源性DBA/2J小鼠中，几种浓度的MLM均未改变基础（Na⁺，K⁺）-ATP酶活性。与C57BL/6J小鼠相比，DBA/2J小鼠中（Na⁺，K⁺）-ATP酶的钾离子激活作用（从3 mM至18 mM）消失，提示胶质细胞（Na⁺，K⁺）-ATP酶受损。在存在MLM（30至1000 mg/L）的情况下，DBA/2J小鼠的皮质（Na⁺，K⁺）-ATP酶可被高浓度钾离子激活，如同在C57BL/6J小鼠中一样。结果表明，MLM在听源性小鼠中的抗癫痫活性可能继发于对缺陷的胶质细胞（Na⁺，K⁺）-ATP酶的激活。
