RESUMO
Isotretinoin (13-cis retinoic acid) is frequently prescribed for severe acne [Peck, G. L., Olsen, T. G., Yoder, F. W., Strauss, J. S., Downing, D. T., Pandya, M., Butkus, D. & Arnaud-Battandier, J. (1979) N. Engl. J. Med. 300, 329-333] but can impair night vision [Fraunfelder, F. T., LaBraico, J. M. & Meyer, S. M. (1985) Am. J. Ophthalmol. 100, 534-537] shortly after the beginning of therapy [Shulman, S. R. (1989) Am. J. Public Health 79, 1565-1568]. As rod photoreceptors are responsible for night vision, we administered isotretinoin to rats to learn whether night blindness resulted from rod cell death or from rod functional impairment. High-dose isotretinoin was given daily for 2 months and produced systemic toxicity, but this caused no histological loss of rod photoreceptors, and rod-driven electroretinogram amplitudes were normal after prolonged dark adaptation. Additional studies showed, however, that even a single dose of isotretinoin slowed the recovery of rod signaling after exposure to an intense bleaching light, and that rhodopsin regeneration was markedly slowed. When only a single dose was given, rod function recovered to normal within several days. Rods and cones both showed slow recovery from bleach after isotretinoin in rats and in mice. HPLC analysis of ocular retinoids after isotretinoin and an intense bleach showed decreased levels of rhodopsin chromophore, 11-cis retinal, and the accumulation of the biosynthetic intermediates, 11-cis and all-trans retinyl esters. Isotretinoin was also found to protect rat photoreceptors from light-induced damage, suggesting that strategies of altering retinoid cycling may have therapeutic implications for some forms of retinal and macular degeneration.
Assuntos
Isotretinoína/farmacologia , Cegueira Noturna/fisiopatologia , Células Fotorreceptoras Retinianas Bastonetes/fisiopatologia , Visão Ocular/efeitos dos fármacos , Animais , Isotretinoína/administração & dosagem , Isotretinoína/uso terapêutico , Luz , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cegueira Noturna/induzido quimicamente , Cegueira Noturna/metabolismo , Ratos , Ratos Sprague-Dawley , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/fisiopatologia , Células Fotorreceptoras Retinianas Bastonetes/efeitos dos fármacos , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Rodopsina/biossínteseRESUMO
PURPOSE: To investigate the possibility that previously demonstrated reductions in photoreceptor sensitivity to light in n-3 fatty-acid-deficient rats can be explained by alterations in rhodopsin content and/or function. METHODS: Sprague-Dawley rats were reared throughout gestation, lactation, and up to 24 weeks of age on a diet containing safflower oil (n-3 fatty-acid-deficient) or soybean oil as the sole source of lipids. Dark-adapted content and in vivo regeneration of rhodopsin after bleaching were measured by detergent extraction. The regeneration rate constants and number of photons absorbed by rhodopsin under steady-state bleach conditions were calculated from these values. The rate of metarhodopsin II (MII) formation in vitro was determined by flash bleaching extracted pigment and native rod outer segment membranes. Rod outer segment length and photoreceptor cell density were determined in histologic sections through the inferior central retina. RESULTS: Dark-adapted rhodopsin content of retinas from rats reared on safflower oil was 12% to 15% higher than that of rats raised on soybean oil at every age measured. The rate of rhodopsin regeneration was significantly slower in rats reared on safflower oil while the level of steady-state bleach was the same. This meant that the rats reared on safflower oil absorbed about one half as many photons during light exposure. The rate of metarhodopsin II formation in vitro was unaffected by n-3 fatty acid deficiency. No difference in either rod outer segment length or cell number was detected. CONCLUSION: A reduced capacity for photon absorption by rhodopsin could play a role in lowering retinal sensitivity to light in n-3 fatty-acid-deficient rats.