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D. Shen, X. Cao, L. Zhao, J. Tuo, W. Wong, C.-C. Chan; Naloxone Ameliorates Retinal Lesions in Ccl2/Cx3cr1 Double Deficient Mice Through Modulation of Microglia. Invest. Ophthalmol. Vis. Sci. 2009;50(13):787.
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© ARVO (1962-2015); The Authors (2016-present)
Naloxone, an opioid receptor antagonist, is able to reduce the pro-inflammatory factors and superoxide generation from LPS-induced microglia activation in CNS. Its role of microglial inhibition and neuroprotective effects has been recently reported in light-induced photoreceptor degeneration. We evaluated the effects of naloxone on the Ccl2-/-/Cx3cr1-/- (DKO) mice, a murine model of age-related macular degeneration (AMD), in which outer retinal lesions associated with microglia accumulation and activation occur.
Two-month old DKO (n = 6) and wild type (WT) controls (n =5) were given daily intraperitoneal injections of naloxone (0.13mg in 0.1 ml PBS) for a period of two months. Three mice of each strain were received PBS only. Funduscopy was performed monthly. After treatment, retinas were analyzed by routine histology and by confocal microscopy in flat-mount preparations immunolabeling of microglial cells with Iba1 antibody. Serum from each mouse was collected for nitrite measurement using Griess colorimetric reaction.
Naloxone ameliorated the progression of retinal lesions in DKO mice. Funduscopic examination scores (range: 0 for no to 4 for severe drusen-like progress) progressed in control DKO mice (increase of 2.3±1.0) but regressed or stable in treated DKO mice (decrease of 0.88±0.9 decrease) from baseline to 2 months of treatment. Histopathology found that fractional retinal area covered by lesions in untreated DKO mice (38.7±8.0%) was higher than in treated DKO mice (20.6±12.2%). No clinical and pathological abnomalities were found in WT mice treated with naloxone. The serum nitrite concentration was 8.3±3.2 µM in untreated WT, 5.7±0.2 in naloxone treated WT (p>0.05); 10.6±3.1 in untreated DKO and 6.4±0.9 in treated DKO mice (p<0.05), respectively. A few (4.5 cells per x 20 field) microglia cells were counted in both groups of WT, in contrast, many (41 cells per x 20 field) microglia cells counted in DKO without treatment, but a significant decrease (9 cells per x 20 field) of microglia cells found in DKO treated with naloxone.
Naloxone significantly reduces retinal lesions in DKO mice. Naloxone modulates microglia accumulation at the site of retinal degeneration, which is possibly mediated via NO. Effects of naloxone on retinal degeneration warrant further investigation. Although the clinical significance of the findings in this study is unknown, the therapeutic potential for the use of naloxone in AMD could be considered.
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