The increased sensitivity of neurons with elevated glucocerebroside to neurotoxic agents can be reversed by imiglucerase

作     者：Pelled, D Shogomori, H Futerman, AH 

作者机构：Weizmann Inst Sci Dept Biol Chem IL-76100 Rehovot Israel 

出 版 物：《JOURNAL OF INHERITED METABOLIC DISEASE》 (遗传代谢疾病杂志)

年 卷 期：2000年第23卷第2期

页      面：175-184页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：Dr Pearl H. Levine Foundation for Research in the Neurosciences 

主　　题：抗代谢药/药理学 羧酸类/药理学 细胞死亡 细胞 培养的 酶抑制剂/毒性 伏马菌素类 戈谢病/酶学 葡糖苷酰鞘氨醇酶/拮抗剂和抑制剂 葡糖苷酰鞘氨醇酶/药理学 葡糖苷酰鞘氨醇类/代谢 海马/细胞学 海马/药物作用 肌醇/类似物和衍生物 肌醇/毒性 神经元/药物作用 神经元/代谢 神经毒素类/毒性 大鼠 Wistar 重组蛋白质类/药理学 动物 大鼠 

摘      要：We have recently demonstrated that incubation of cultured rat hippocampal neurons with conduritol beta-epoxide (CBE), an inhibitor of glucocerebrosidase, the enzyme defective in Gaucher disease, results in changes in intracellular morphology and in functional calcium stores. Changes in levels of functional calcium stores are directly related to neuronal cell death. We now show that neurons incubated with either CBE or a non-hydrolysable analogue of GlcCer (glucosylthioceramide), are more sensitive to the toxic effects of high concentrations of glutamate and of a variety of metabolic inhibitors. A linear relationship exists between level of accumulation of GlcCer and the extent of neuronal cell death. The deleterious effects of elevated GlcCer levels can be completely reversed by addition of human glucocerebrosidase (imiglucerase) to the culture medium. Imiglucerase is internalized to lysosomes, where it presumably degrades excess GlcCer. This suggests that the limited success of enzyme replacement therapy in neuronopathic forms of Gaucher disease is not due to lack of efficacy of glucocerebroside in degrading GlcCer in neurons of the central nervous system, and adds impetus to attempts to develop ways to efficiently deliver glucocerebrosidase to the brains of neurologically compromised Gaucher disease patients.