Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway.
Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway.
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DOI：
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发表时间：
1999
影响因子：
4.4
通讯作者：
John E. Heng;C. Vorwerk;Ephraim Lessell;D. Zurakowski;Leonard A. Levin;Evan B. Dreyer
中科院分区：
文献类型：
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作者：
John E. Heng;C. Vorwerk;Ephraim Lessell;D. Zurakowski;Leonard A. Levin;Evan B. Dreyer
目的乙胺丁醇是治疗结核病的重要药物。然而，它可能导致病因不明的视神经病变。因此，在啮齿动物视网膜细胞中研究了乙胺丁醇毒性，并考虑了可能阻止其毒性的药物。方法 在啮齿动物视网膜分离细胞制剂和全眼中评估乙胺丁醇和相关药物的毒性。通过荧光和染色技术评估钙通量和线粒体功能。对于体内测定，成年大鼠在三个月内口服乙胺丁醇。通过体视学评估细胞存活率。结果乙胺丁醇在体外和体内对视网膜神经节细胞具有特异性毒性。内源性谷氨酸对于乙胺丁醇毒性的充分表达是必需的，谷氨酸拮抗剂可防止乙胺丁醇介导的细胞损失。乙胺丁醇导致细胞溶质钙减少、线粒体钙增加和线粒体膜电位增加。结论 与乙胺丁醇相关的视力丧失可能是通过兴奋性毒性途径介导的，因为神经节细胞对正常耐受的细胞外谷氨酸水平敏感。乙胺丁醇会干扰线粒体功能。其毒性可能取决于 ATP 酶活性和线粒体能量稳态的降低。谷氨酸拮抗剂可能有助于限制乙胺丁醇的副作用。
PURPOSE Ethambutol is an essential medication in the management of tuberculosis. However, it can cause an optic neuropathy of uncertain etiology. Ethambutol toxicity was therefore studied in rodent retinal cells, and agents that might block its toxicity were considered. METHODS The toxicity of ethambutol and related agents was evaluated in rodent retinal dissociated cell preparations and whole eyes. Calcium fluxes and mitochondrial function were evaluated by fluorescent and staining techniques. For in vivo assays, adult rats were administered oral ethambutol over a 3-month period. Cell survival was assessed by stereology. RESULTS Ethambutol is specifically toxic to retinal ganglion cells in vitro and in vivo. Endogenous glutamate is necessary for the full expression of ethambutol toxicity, and glutamate antagonists prevent ethambutol-mediated cell loss. Ethambutol causes a decrease in cytosolic calcium, an increase in mitochondrial calcium, and an increase in the mitochondrial membrane potential. CONCLUSIONS The visual loss associated with ethambutol may be mediated through an excitotoxic pathway, inasmuch as ganglion cells are rendered sensitive to normally tolerated levels of extracellular glutamate. Ethambutol perturbs mitochondrial function. Its toxicity may depend on decreased ATPase activity and mitochondrial energy homeostasis. Glutamate antagonists may be useful in limiting the side effects seen with ethambutol.