Protective effect of idebenone on ethambutol-induced optic neuropathy in R28 cells and mice
Other Titles
에탐부톨 시신경병증의 R28 cell과 마우스 모델에서 이데베논의 보호 효과
Authors
한진우
College
Graduate School, Yonsei University
Department
Dept. of Medicine
Degree
박사
Issue Date
2017
Abstract
Ethambutol is an anti-tuberculosis medication that induces retinal ganglion cell
injury in the visual system. Oxidative stress and mitochondrial dysfunction are
widely accepted as possible pathogenic mechanisms of ethambutol-induced
optic neuropathy. Idebenone, a Coenzyme Q-10 derivate, is a potent free radical
scavenger with demonstrated neuroprotective effect in experimental models of
Leber’s hereditary optic neuropathy, which shares common clinical features
with ethambutol-induced optic neuropathy. The present study was designed to
investigate whether idebenone could provide protective effect against
ethambutol-induced optic neuropathy in R28 cell line and mice. The cultured
R28 cell lines were pretreated with different dose of idebenone for 24h,
followed by the challenge with 3mM ethambutol for 24h. Exposure of
ethambutol caused the loss of cell viability and the ATP content with
dose-dependent manner in R28 cell. Idebenone pretreatment had protective
effect on cell survival and ATP contents in ethambutol induced neuronal death
of R28 cells. However, we demonstrated that ethambutol exposure did not
significantly elevate intracellular reactive oxygen species generation and
mitochondria-derived superoxide production, and it had no effect on
mitochondrial membrane potential. However, zinc accumulation in lysosome
and microtubule associated protein 1 light chain 3 were increased with ethambutol treatment, which were efficiently attenuated by idebenone
pretreatment. In mouse model, 200mg/kg ethambutol was injected
intraperitoneally alternate day for 6 weeks and 200mg/kg idebenone was
introduced with oral gavage. Idebenone had a slight protective effect of visual
function in mouse model, which was tested by optomotor test. However, it
failed to demonstrate a beneficial effect on ganglion cell structure by optical
coherence tomography, and photopic negative response was not differ among
groups. In conclusion, these results suggest that idebenone has a mild protective
effect against ethambutol-induced neurotoxicity, and these beneficial effects of
idebenone may be attributable to its roles on lysosomal zinc accumulation, not
directly in preventing reactive oxygen species.