title: Retinal function and morphology in monkeys with ethambutol-induced optic neuropathy.
abstract: OBJECTIVE
  Ethambutol-induced optic neuropathy is a well recognized adverse ocular event. However, abnormalities of the retina in this optic neuropathy are not fully understood. Therefore, the purpose of the present study was to investigate both functional and morphological alterations of the retina induced by ethambutol in monkeys.
  
  
  METHODS
  Ethambutol was orally administered to three cynomolgus monkeys, initially at 400 mg/kg/day followed by 800 mg/kg/day, for a maximum of 39 weeks. Full-field electroretinograms (ERGs) were recorded at intervals of approximately one month. The protocol included standard ERG responses to white flashes obtained under dark-adapted conditions (rod, combined rod-cone, oscillatory potentials) or with a white background (single-flash cone, 30 Hz flicker). In addition, we measured the ERG elicited with red flashes under blue background light (single-flash cone response [R/B]). All the ethambutol-treated monkeys were euthanized, and the retinae and various other nervous system tissues were examined histopathologically.
  
  
  RESULTS
  No obvious changes were observed in the standard full-field ERGs. On the other hand, selective attenuation of the photopic negative response (PhNR) of the single-flash cone response (R/B) was observed in two out of three ethambutol-treated monkeys at week 22 or 28. Histopathology of these two monkeys revealed single cell necrosis of the retinal ganglion cells (RGCs), decreased RGCs in the parafovea and increased microglial cells in the nerve fiber layer in the retina, in addition to demyelination and glial reaction in the optic nerve, chiasm and tracts.
  
  
  CONCLUSIONS
  The attenuated PhNR and histopathology of the retina indicated that RGCs were markedly damaged, both functionally and morphologically in monkeys with ethambutol-induced optic neuropathy. These results implied that RGCs are predominantly affected in the retina of patients with ethambutol-induced optic neuropathy.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Shizuoka, Japan. kinoshita.junzo.dy@daiichisankyo.co.jp
authors.forename: Junzo
authors.initials: J
authors.lastname: Kinoshita
authors.forename: Noriaki
authors.initials: N
authors.lastname: Iwata
authors.forename: Takanori
authors.initials: T
authors.lastname: Maejima
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Kimotsuki
authors.forename: Mitsuya
authors.initials: M
authors.lastname: Yasuda
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity; D003623:Dark Adaptation; D004195:Disease Models, Animal; D004596:Electroretinography; D004977:Ethambutol / Q000633:toxicity; D008252:Macaca fascicularis; D017628:Microglia / Q000187:drug effects / Q000473:pathology*; D009336:Necrosis; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology*; D009901:Optic Nerve Diseases / Q000139:chemically induced / Q000503:physiopathology*; D010775:Photic Stimulation; D012160:Retina / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology*
chemical_list: D000995:Antitubercular Agents; D004977:Ethambutol