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E.H. Hughes, F.C. Schlichtebrede, C.C. Murphy, R.R. Ali, A.D. Dick; Minocycline Suppresses Photoreceptor Apoptosis in the rds Mouse Through a Mechanism Unrelated to Microglial Inhibition . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2843.
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Purpose: Increased microglial numbers in the outer retinal layers during photoreceptor degeneration and an increasing awareness of their cytotoxic potential have implicated microglia in contributing to photoreceptor death. To elucidate further we have chosen two approaches: (i) administration of minocycline, a known inhibitor of microglial activation and of apoptosis via caspase 1 and 3 inhibition, and (ii) administration of liposomal clodronate capable of macrophage depletion and inhibition of microglial recruitment. Methods: From birth, rds mice were treated intra-peritoneally with either daily minocycline or alternate day liposomal clodronate until age 16 and 21 days. Immunohistochemistry illustrated retinal microglial numbers (F4/80) and extent of photoreceptor apoptosis (TUNEL). Results: In comparison with untreated sibling controls, minocycline treatment produced a reduction in both microglial numbers (by 50%) and photoreceptor apoptosis (by 66%) at day 16 (p<0.01), when photoreceptor apoptosis is greatest in rds mice. Treatment with liposomal clodronate, however, despite a significant depletion of retinal microglia had no effect upon photoreceptor apoptosis. Conclusions: Minocycline has inhibitory effects on both apoptosis and microglial activation and was able to reduce photoreceptor apoptosis at the peak of disease in this model by 66%. Since depletion of retinal microglia with liposomal clodronate does not influence photoreceptor apoptosis, the beneficial effect of minocycline is probably due to its inhibition of caspase rather than any associated reduction in microglial numbers. These results reveal a potential therapeutic value of minocycline in retinal degenerations and provide further evidence that microglia are innocent of the early wave of photoreceptor apoptosis in the rds mouse.
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