Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway.

PubMed ID: 9888443

Author(s): Heng JE, Vorwerk CK, Lessell E, Zurakowski D, Levin LA, Dreyer EB. Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway. Invest Ophthalmol Vis Sci. 1999 Jan;40(1):190-6.

Journal: Investigative Ophthalmology & Visual Science, Volume 40, Issue 1, Jan 1999

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.