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Paul Yang, Rachel Lockard, Yuquan Wen, Richard G Weleber, Mark E Pennesi; Mycophenolate mofetil is neuroprotective in a mouse model of retinitis pigmentosa (RP). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3620.
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© ARVO (1962-2015); The Authors (2016-present)
Previous evidence in rodent models of RP implicated the role of cGMP cytotoxicity and immune-mediated damage from microglia activation and expression of inflammatory cytokines. Mycophenolate mofetil (MMF), a commonly-used immunomodulatory medication in ocular immunology, is known to deplete precursors of cGMP and inhibit microglia activation. We hypothesize that MMF is neuroprotective in the rd10 mice.
The rd10 mice received daily i.p. injections of MMF or vehicle (5% dextrose, D5) prior to any structural evidence of retinal degeneration. Optical coherence tomography (sdOCT) was used to quantify retinal thickness as previously described (Pennesi et al., IOVS, 2012). Postnatal day (p) 22 mice were euthanized and eyes were harvested for IHC. Fixed, OCT-embedded eyes were cryosectioned, mounted, and stored at -200 C. Anti-arrestin and DAPI were used to stain photoreceptors and nuclei, respectively. Anti-CD11b and -F4/80 were used as microglia markers, and anti-TNFɑ was used to assess for inflammation. Two-tailed Student’s t-test was used for statistical analysis.
The rd10 mice that were treated with MMF 100 mg/kg/d (n=7, 117.3 ± 1.1 µm) from p13-p22 not only had significantly greater outer retinal thickness compared with the D5 group (n=6, 68.9 ± 8.1 µm; p=0.002), but had similar thickness as age-matched c57 mice (n=4, 122.3 ± 1.4 µm); IHC showed normal outer retinal structure with no signs of microglia activation in the MMF group compared with the microglia-laden atrophic retina in the D5 group (figure 1,2). When treatment was initiated just one day later from p14-p22, the neuroprotective effect of MMF on outer retinal thickness was less prominent (n=11, 73.7 ± 6.4 µm), although still significant compared with the D5 group (n=13, 46.8 ± 1.6 µm; p=0.001).
Treatment with MMF showed significant neuroprotection in rd10 mice, producing robust structural preservation of the retina without signs of microglia activation. The neuroprotective effect was enhanced by earlier treatment, suggesting a critical window of opportunity for therapy. Further examination will be needed to elucidate the neuroprotective mechanisms of MMF.
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