Controlled delivery of tauroursodeoxycholic acid from biodegradable microspheres slows retinal degeneration and vision loss in P23H rats

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.

Cannabinoid-mediated retinal rescue correlates with improved circadian parameters in retinal dystrophic rats

“…The protective effects of synthetic cannabinoid HU210 on the retina of dystrophic P23H rats agree with a previous study of our group demonstrating that cannabinoids preserve the structure and function of the retina in P23H rats (Lax et al, 2014), and with other earlier studies in which we assessed the neuroprotective effects of antioxidant and antiapoptotic agents (Fernandez-Sanchez et al, 2017;Fernandez-Sanchez et al, 2012a;Fernandez-Sanchez et al, 2012b;Fernandez-Sanchez et al, 2015;Fernandez-Sanchez et al, 2011;Roche et al, 2016).…”

“…Histological studies were conducted at P90, after ERG recording. Vertical cryostat sections were prepared, according to procedures that are well-established in the literature (Fernandez-Sanchez et al, 2017;Noailles et al, 2016). Animals were sacrificed in the morning with a lethal dose of pentobarbital sodium.…”

Retinal Cell Protection in Ocular Excitotoxicity Diseases. Possible Alternatives Offered by Microparticulate Drug Delivery Systems and Future Prospects

“…Tauroursodeoxycholic acid (TUDCA), the most important component of bear bile (Ursus thibetanus or Selenarctos thibetanus, also known as the Moon bear due to its coat markings [66]) has been shown to display cytoprotective and antiapoptotic effects in rodent models of retinal degeneration [14]. The mechanism of action is not fully understood though it seems to block apoptosis at various levels, including the alleviation of endoplasmic reticulum stress, the stimulation of the PI3K and MAPK (p38, ERK1/2) survival pathways and the blockade of Bax translocation to the mitochondria impeding subsequent cytochrome c release.…”

“…Excitotoxicity has been linked to the pathogenesis of several serious degenerative ocular diseases and injuries [9]. Apart from glaucoma, retinitis pigmentosa [14], diabetic retinopathy [15], retinal ischemia [16], age-related macular degeneration (AMD) [17] or Leber hereditary optic neuropathy are characterized by progressive retinal neurodegeneration. These disorders include cell stress and inflammatory response, at least in part due to increased glutamate levels [18], what ends in retinal remodeling.…”

“…They emerge as an interesting alternative to repeated intravitreal injections of active substances in solution [33]. The administration of IODDS not only avoids serious complications related to frequent repeated injections, i.e., endophthalmitis and retinal detachment [34], but also reduces the risk of initial toxicity, due to high local drug concentrations typically occurring when they are administered in bolus [14]. Because of their micro-and nano-sized dimensions, the use of particulate systems has been explored as an appropriate alternative to conventional options in ophthalmology.…”