title: Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Ophthalmology, Harvard University, Boston, Massachusetts, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Heng
authors.forename: C K
authors.initials: CK
authors.lastname: Vorwerk
authors.forename: E
authors.initials: E
authors.lastname: Lessell
authors.forename: D
authors.initials: D
authors.lastname: Zurakowski
authors.forename: L A
authors.initials: LA
authors.lastname: Levin
authors.forename: E B
authors.initials: EB
authors.lastname: Dreyer
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004977:Ethambutol / Q000633:toxicity*; D005029:Ethylenediamines / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005456:Fluorescent Dyes; D018698:Glutamic Acid / Q000378:metabolism*; D008559:Memantine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000502:physiology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D051381:Rats; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; C101089:CM-DiI; D002232:Carbocyanines; D005029:Ethylenediamines; D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D013778:Tetrazolium Salts; D013844:Thiazoles; D018698:Glutamic Acid; C030779:EDBA; D016202:N-Methylaspartate; D004977:Ethambutol; C022616:thiazolyl blue; D002118:Calcium; D008559:Memantine