ABSTRACT
Retinal toxicity of chloroquine has been known for several years, but the mechanism(s) of toxicity remain controversial; some author support the idea that the binding of chloroquine to melanin pigments in the retinal pigmented epithelium (RPE) play a major toxic role by concentrating the drug in the eye. In our study, 12 albinos Sprague-Dawley (SD) and 12 pigmented Brown Norway (BN) rats were treated orally for 3 months with chloroquine to compare functional and pathological findings. On Flash electroretinograms (ERG) performed in scotopic conditions, similar and progressive (time-dependent) delayed onset and decreased amplitudes of oscillatory potentials (from Day 71) and b-waves (on Day 92) were identified in both BN and SD rats. In both strains, identical morphological changes consisted of neuronal phospholipidosis associated with UV auto-fluorescence without evidence of retinal degeneration and gliosis; the RPE did not show any morphological lesions or autofluorescence. IHC analyses demonstrated a decrease in GABA expression in the inner nuclear layer. In addition, a marked accumulation of synaptic vesicles coupled with a marked disruption of neurofilaments in the optic nerve fibers was identified. In conclusion, ERG observations were very similar to those described in humans. Comparable ERG modifications, histopathology and immunohistochemistry findings were observed in the retina of both rat strains suggesting that melanin pigment is unlikely involved. chloroquine-induced impairment of synaptic vesicle transport, likely related to disruption of neurofilaments was identified and non-previously reported. This new mechanism of toxicity may also be responsible for the burry vision described in humans chronically treated with chloroquine.
Subject(s)
Chloroquine/toxicity , Neurons/metabolism , Phospholipids/metabolism , Retina/metabolism , Synaptic Vesicles/metabolism , Animals , Biological Transport/drug effects , Biological Transport/physiology , Electroretinography/methods , Male , Neurons/drug effects , Neurons/pathology , Rats , Rats, Inbred BN , Rats, Sprague-Dawley , Retina/drug effects , Retina/pathology , Species Specificity , Synaptic Vesicles/drug effects , Synaptic Vesicles/pathologyABSTRACT
Confocal scanning laser ophthalmoscope (cSLO) is a new technique which enables ocular fundus image recording and dynamic retinal angiography to be performed. The ocular fundus image is acquired sequentially, point by point, and is reconstructed on a video monitor at the rate of 25 images per second. The aim of this paper is to evaluate the feasibility of measuring retinal arterio-venous filling times (AVFT) with a I + Tech cSLO. Three young adult cynomolgus monkeys and three young adult Göttingen minipigs were used as experimental models. All animals were anesthetized using a zolazepam + tiletamine mixture injected intramuscularly; heart rate and rectal temperature were monitored and corneal irrigation was regularly performed. For all subjects, prior to examination, hematocrit and globe axial length were measured. The images were recorded, stabilized and analyzed. The retinal examination consisted of retinal images with 40 degrees field cSLO, retinal fluorescein angiography and arterio-venous 50% filling time measurements. For each subject all images were easily recorded while keeping the animals in a normally lighted room without having to use any additional optical device. AVFT using an I + Tech cSLO is easily performed in monkeys and minipigs. AVFT measurements in minipigs and monkeys are similar. These results suggest that minipigs can replace monkeys as an experimental species for AVFT investigations.
