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J. N. Edmonds, F. N. Ross-Cisneros, V. Carelli, A. A. Sadun; Chloramphenicol-Induced Optic Neuropathy in a Mouse Model: An Ultrastructural Study. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4362. doi: https://doi.org/.
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Chloramphenicol, an antibiotic known to inhibit mitochondrial protein synthesis, causes optic neuropathy in humans with long term use. This study investigates the effects of respiratory chain dysfunction induced by chloramphenicol on the ultrastructural characteristics of the mouse optic nerve.
Adult BL6J mice (age 3 months) were treated with chloramphenicol succinate p.o. for 15 days at 500 mg/kg/day and 1000 mg/kg/day. A third group which received vehicle (without drug) served as a control. Tissues were immersion fixed in mixed aldehydes containing gluteraldehyde. Optic nerves were processed and embedded in plastic blocks as cross-sectional profiles. Thin sections were obtained with the use of an ultramicrotome, stained with uranyl acetate and lead citrate, and examined with a transmission electron microscope (TEM) for ultrastructural features of optic nerve morphology.
In both treated groups condensation and atrophy of axons was evident as compared to controls. Increases in astrocyte number and size were also observed in both treated groups. Profiles of axons circumscribed by cytoplasmic tongues wrapped by thin layers of myelin externally was often noted in close proximity to oligodendrocytes. Oligodendrocytes appeared to be the primary cell undergoing degenerative changes as observed by their nuclei undergoing various levels of pyknosis, as well as condensation and involution of their cytoplasm. Macrophages possessing cellular debris were also seen extending their processes through these degenerative zones. Mitochondrial morphology appeared to be normal in the treatment groups, but increases in mitochondrial number was also discovered.
Chloramphenicol at high doses for a short duration (15 days) resulted in observable disruption of the mouse optic nerve at the ultrastructural level, characterized by profiles of axonal condensation and nerve fiber degeneration, remyelination, neuroglial reactivity and cell death. Gliotic changes were the most pronounced morphological evidence for cell injury as observed by astrocytic hypertrophy and hyperplasia (gliosis), oligodendrocytic remyelination of demyelinated (denuded) axons and apoptotic changes. Furthermore, we hypothesize that the increase in the number of mitochondria observed in both treated groups was a compensatory reaction to the effects of chloramphenicol’s ability to suppress mitochondrial protein synthesis.
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