flunarizine and Retinal-Degeneration

Free radical scavengers and a calcium overload blocker have been demonstrated separately to ameliorate light-induced retinal degeneration, suggesting that both free radical formation and increased intracellular calcium levels are involved in the pathologic changes of this disease process. To understand the relationship between these two mechanisms, we studied the ameliorative effects of combined treatment with flunarizine and dimethylthiourea as well as individual treatment with either drug in a rat model of light-induced retinal degeneration. At 6 hr and 6 and 14 days after light exposure, morphologic and morphometric studies of the retinas from the rats receiving the combined treatment demonstrated better-preserved retinal pigment epithelial cells, photoreceptor elements, and nuclei than did retinas from rats receiving treatment with either flunarizine or dimethylthiourea alone. Rhodopsin level measurements at 6 and 14 days further substantiated the results of the protective effects on the photoreceptor outer segments. Because we used a saturating dose for dimethylthiourea, the enhanced ameliorative effect of the combination treatment suggested that free radical formation and elevated intracellular calcium levels were two separate mechanisms in light-induced retinal degeneration.

Topics: Animals; Drug Therapy, Combination; Flunarizine; Light; Male; Rats; Rats, Inbred Lew; Retina; Retinal Degeneration; Thiourea

Although free radical formation and lipid peroxidation have been implicated in photoreceptor degeneration following continuous light exposure, recent evidence led us to hypothesize that excessive stimulation of the photoreceptor cells in prolonged light exposure may cause intracellular calcium overload and consequent photoreceptor cell injury. To test this hypothesis, we studied the effects of flunarizine hydrochloride, a calcium overload blocker that inhibits the inositol 1,4,5-triphosphate-induced release of intracellular stores of calcium, in an established rat model of light-induced retinal degeneration. Light and electron microscopic examination of the flunarizine-treated retinas revealed remarkable preservation of the retinal pigment epithelium, rod inner and outer segments, nuclei, and synapses of the photoreceptor cells at all phases of the recovery period. This observation was further supported by morphometric evaluation of the outer nuclear layer thickness, which revealed a greater preservation of the photoreceptor nuclei in the drug-treated animals at 6 and 14 days after exposure. In addition, the rhodopsin levels in the flunarizine-treated retinas were also significantly higher than in the controls in all phases of recovery. The ability of flunarizine to ameliorate light-induced retinal degeneration in the rat supports our hypothesis that elevated intracellular calcium may indeed play a role in light-induced photoreceptor degeneration.

Topics: Animals; Calcium; Disease Models, Animal; Flunarizine; Light; Photoreceptor Cells; Rats; Rats, Inbred Lew; Retina; Retinal Degeneration; Rhodopsin