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Paul Yang, Hope Titus, Kyle Weller, Robert Duvoisin, Richard Weleber, Catherine W Morgans, Mark E Pennesi; Early Treatment with Mycophenolate Reduces Microglial Migration in rd10 mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):453. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The rd10 mouse is the prototypical model of retinitis pigmentosa, wherein primary cGMP dysregulation and secondary immune-mediated damage via microglia activation are implicated as mechanisms of retinal degeneration. Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid (MPA), a commonly-used drug in uveitis, which has been shown to inhibit microglial activation in-vitro. We previously showed that MMF mitigates cGMP dysregulation in rd10 mice. We hypothesize that MMF or MPA inhibits microglia activation and migration into the outer retina.
Rd10 mice were treated with systemic MMF (100 mg/kg/day, i.p.) from P12-22. Rd10 and c57 mice were treated with a single one microliter injection of intravitreal MPA (0.05 μg) in one eye and vehicle injection (0.4% polysorbate 80, 0.5% hydroxypropyl methylcellulose) in the contralateral eye at the earliest age of eye-opening, P13. Optical coherence tomography (OCT) was used to quantify outer retinal thickness, and ERG was used to assess retinal function. IHC was used to assess whole mounts for microglia morphology and density in the outer retinal layers. Each quadrant of the whole mount IHC was imaged with confocal microscopy, the outer retinal layers were z-stacked, and counted by a masked grader. ANOVA and Welch’s t test was used for comparisons.
Compared with naïve animals, systemic treatment of rd10 mice with MMF 100 mg/kg initiated at P12 significantly reduced the density of microglia counts in the outer retinal layers (29.5 ±4.1 vs. 48.4 ±3.1, p =0.002). In c57 mice, intravitreal MPA at P13 had no detrimental effect on OCT or ERG compared with the contralateral vehicle-injected eye. However, a single intravitreal injection of MPA at P13 also had no effect on rd10 mice by P22.
Early systemic daily treatment with MMF significantly reduced microglial migration into the outer retina in rd10 mice. A single intravitreal injection of MPA at P13 was safe, but not beneficial in rd10 mice. Additional experiments are underway to determine if earlier treatment or repeated injections with higher dose MPA are neuroprotective in rd10 mice.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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