Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway

PURPOSE. Ethambutol is an essential medication in the management of tubercu losis. However, it can cause an optic neuropathy of uncertain etiology. Eth ambutol 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 rod ent retinal dissociated cell preparations and whole eyes. Calcium fluxes an d mitochondrial function were evaluated by fluorescent and staining techniq ues. 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 vitr o 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 pot ential. CONCLUSIONS. The visual loss associated with ethambutol may be mediated thr ough an excitotoxic pathway, inasmuch as ganglion cells are rendered sensit ive to normally tolerated levels of extracellular glutamate. Ethambutol per turbs mitochondrial function. Its toxicity may depend on decreased ATPase a ctivity and mitochondrial energy homeostasis. Glutamate antagonists map be useful in limiting the side effects seen with ethambutol.