Abstract
Successful drug therapies for treating ocular diseases require effective concentrations of neuroprotective compounds maintained over time at the site of action. The purpose of this work was to assess the efficacy of intravitreal controlled delivery of tauroursodeoxycholic acid (TUDCA) encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres for the treatment of the retina in a rat model of retinitis pigmentosa. PLGA microspheres (MSs) containing TUDCA were produced by the O/W emulsion-solvent evaporation technique. Particle size and morphology were assessed by light scattering and scanning electronic microscopy, respectively. Homozygous P23H line 3 rats received a treatment of intravitreal injections of TUDCA-PLGA MSs. Retinal function was assessed by electroretinography at P30, P60, P90 and P120. The density, structure and synaptic contacts of retinal neurons were analyzed using immunofluorescence and confocal microscopy at P90 and P120. TUDCA-loaded PLGA MSs were spherical, with a smooth surface. The production yield was 78%, the MSs mean particle size was 23 μm and the drug loading resulted 12.5 ± 0.8 μg TUDCA/mg MSs. MSs were able to deliver the loaded active compound in a gradual and progressive manner over the 28-day in vitro release study. Scotopic electroretinografic responses showed increased ERG a- and b-wave amplitudes in TUDCA-PLGA-MSs-treated eyes as compared to those injected with unloaded PLGA particles. TUDCA-PLGA-MSs-treated eyes showed more photoreceptor rows than controls. The synaptic contacts of photoreceptors with bipolar and horizontal cells were also preserved in P23H rats treated with TUDCA-PLGA MSs. This work indicates that the slow and continuous delivery of TUDCA from PLGA-MSs has potential neuroprotective effects that could constitute a suitable therapy to prevent neurodegeneration and visual loss in retinitis pigmentosa.
Highlights
Posterior segment eye diseases are a major cause of blindness in the world
The present study shows that PLGA microspheres containing low doses of tauroursodeoxycholic acid (TUDCA), when intravitreally administered, were able to slow vision loss and retinal remodeling in an animal model of retinal degeneration
The method described here allowed for the stabilization and controlled release of TUDCA encapsulated in poly(D,L-lactic-co-glycolic acid) microspheres, providing long-term intraocular delivery of the compound, and ensuring neuroprotective effects in the posterior segment of the eye
Summary
Posterior segment eye diseases are a major cause of blindness in the world. Retinitis pigmentosa (RP) is a large and heterogeneous group of genetic disorders characterized by progressive retinal neurodegeneration. The most important component of bear bile, tauroursodeoxycholic acid (TUDCA), has been shown to display antiapoptotic effects in rodent models of retinal degeneration, including retinal light damage [25], experimental retinal detachment [26], elevated glucose-induced retinal damage [27], oxidative stress-induced retinal degeneration [28], retinitis pigmentosa [29,30,31,32,33], Leber congenital amaurosis [34, 35], and retinal ganglion cell (RGC) death models [36] In these models of retinal disease, systemic administration of TUDCA significantly reduced retinal neurons death and improved retinal morphology and function. TUDCA has been demonstrated to be useful as an cytoprotective and antiapoptotic agent in other neurodegenerative disorders, including Huntington’s [37], Parkinson’s [38, 39] and Alzheimer’s diseases [40], in human patients with amyotrophic lateral sclerosis [41], and in models of prion disease [42]
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