Minocycline treatment reduces the activation of mononuclear phagocytes and improves retinal function in a mouse model of Leber congenital amaurosis.

Abstract

Purpose: Leber congenital amaurosis (LCA) is a severe hereditary retinal degeneration characterized by early-onset vision loss. Here, we aimed to characterize the association between retinal mononuclear phagocyte (MP) activation and retinal degeneration in the RPE65/rd12 mouse model of LCA.

Methods: Thirty-nine RPE65/rd12 and ten C57BL/6J wild-type mice were used. RPE65/rd12 mice were treated with minocycline by daily intraperitoneal injection (5 mg/kg) for eight weeks starting at age postnatal day 28 (P28). MP cell density in the subretina was determined by choroid-retinal pigment epithelium (RPE) flat mount analysis, and retinal function was determined by electroretinogram (ERG).

Results: In wild-type C57BL/6J mice, MPs were exclusively located in the inner retinal layers at ages P28-P84. By contrast, in the RPE65/rd12 mice, MPs migrated into the subretina as early as P56 in a central-to-peripheral gradient. By P84, the density of MPs in the subretina increased by nearly 3-fold, reaching 61.3 ± 6.2 cell/mm² and 33.1 ± 8 cell/mm² in the central and peripheral retina, respectively. Minocycline treatment significantly reduced MP density in the peripheral subretina (16.2 ± 1.8 MP cell/mm²) compared with mice treated with PBS (27.2 ± 2.4 MP cell/mm², respectively, p = 0.006). Maximal electroretinogram b-wave responses were significantly higher in minocycline- vs. PBS-treated mice under light-adapted conditions following eight weeks of treatment (mean ± SE: 199µv ± 28µv vs. 129.8µv ± 9.8µv, p = 0.016).

Conclusions: Our data indicates that MP migration into the subretina is associated with retinal degeneration in RPE65/rd12 mice. Inhibiting MP migration into the subretina was associated with improved retinal function. These findings may guide the development of therapies targeting MP activation for neuroprotection in LCA and potentially other retinoid cycle-related retinal degeneration blinding diseases.