Ag
S nanoparticles (NPs) emerge as a unique system that simultaneously features in vivo near-infrared (NIR) imaging, remote heating, and low toxicity thermal sensing. In this work, their capabilities ...are extended into the fields of optical coherence tomography (OCT), as contrast agents, and NIR probes in both ex vivo and in vivo experiments in eyeballs. The new dual property for ocular imaging is obtained by the preparation of Ag
S NPs ensembles with a biocompatible amphiphilic block copolymer. Rather than a classical ligand exchange, where surface traps may arise due to incomplete replacement of surface sites, the use of this polymer provides a protective extra layer that preserves the photoluminescence properties of the NPs, and the procedure allows for the controlled preparation of submicrometric scattering centers. The resulting NPs ensembles show extraordinary colloidal stability with time and biocompatibility, enhancing the contrast in OCT with simultaneous NIR imaging in the second biological window.
Enzyme glycogen synthase kinase-3 (GSK-3) is a candidate pharmacological target for the treatment of neurodegenerative diseases of the brain. Given the many molecular, cellular, and functional ...features shared by the brain and the retina in both physiological and pathological processes, drugs originally designed to treat neurodegenerative diseases of the brain could be useful candidates for the treatment of retinal degenerative pathologies. Moreover, the accessibility of the eye to noninvasive, quantitative diagnostic techniques allows for easier evaluation of the efficacy of candidate therapies in clinical trials. In this chapter, we discuss the potential of GSK-3 inhibitors in the treatment of retinal degeneration.
Purpose: The photoreceptor degeneration associated to retinitis pigmentosa (RP) is caused by a wide variety of genetic mutations, which greatly complicates the development of a universal effective ...treatment. As a process independent of the causative mutation, the inflammatory response resulting from neuronal death could represent a potential candidate for a general treatment for RP. In this context, we studied the role of TLR4, one of the main mediators of innate immunity, on the retinal degenerative process in two murine models of RP.
Methods: rd10 and P23H/+ mice were used to evaluate the consequences of Tlr4 haploinsufficiency and complete deletion on retinal degeneration. Visual function was evaluated by electroretinographic recordings and optomotor test and retinal cytoarchitecture by immunohistology. The myeloid cell population (main mediators of the innate immune response) reactivity was studied by immunohistology and flow cytometry. Gene expression was assessed by RT‐quantitative PCR.
Results: We found that Tlr4 expression was significantly increased in the retina of both RP models. To assess the effect of Tlr4 deletion in PR progression first we confirmed that abrogation of Tlr4 expression did not impair visual function in wild‐type animals. However, Tlr4 deficiency accelerated RP progression in both rd10 and P23H/+ mice. Deletion of a single Tlr4 allele reduced the retinal electroretinographic response and photoreceptor survival in both RP models. Moreover, complete abrogation of Tlr4 further exacerbates this phenotype. These results were confirmed by assessing visual acuity by optomotor test in P23H/+ mice. Microglia analysis showed higher proportion of phagocytic microglia and lower of homeostatic microglia in the photoreceptor layers upon Tlr4 total deletion.
Conclusions: The TLR4 receptor exerts a neuroprotective effect on the retinal neurodegenerative process in RP, thus suggesting a potential therapeutic target for the disease.
Ag2S nanoparticles (NPs) emerge as a unique system that simultaneously features in vivo near‐infrared (NIR) imaging, remote heating, and low toxicity thermal sensing. In this work, their capabilities ...are extended into the fields of optical coherence tomography (OCT), as contrast agents, and NIR probes in both ex vivo and in vivo experiments in eyeballs. The new dual property for ocular imaging is obtained by the preparation of Ag2S NPs ensembles with a biocompatible amphiphilic block copolymer. Rather than a classical ligand exchange, where surface traps may arise due to incomplete replacement of surface sites, the use of this polymer provides a protective extra layer that preserves the photoluminescence properties of the NPs, and the procedure allows for the controlled preparation of submicrometric scattering centers. The resulting NPs ensembles show extraordinary colloidal stability with time and biocompatibility, enhancing the contrast in OCT with simultaneous NIR imaging in the second biological window.
In recent years, Ag2S nanoparticles have shown great potential in nanomedicine, specifically in areas such as near‐infrared (NIR) imaging, photothermal therapy, and photoluminescence nanothermometry. In this work, biocompatible and size‐controlled ensembles of Ag2S nanoparticles demonstrate their great dual performance as bright NIR probes and enhancers of the optical coherence tomography signals in ex vivo and in vivo studies.
Insulin-degrading enzyme (IDE) was named after its role as a proteolytic enzyme of insulin. However, recent findings suggest that IDE is a widely expressed, multitask protein, with both proteolytic ...and non-proteolytic functions. Here, we characterize the expression of IDE in the mammalian retina in both physiological and pathological conditions. We found that IDE was enriched in cone inner segments. IDE levels were downregulated in the dystrophic retina of several mouse models of retinitis pigmentosa carrying distinct mutations. In
mice, a commonly studied mouse model of retinitis pigmentosa, treatment with an IDE activator (a synthetic peptide analog of preimplantation factor) delayed loss of visual function and preserved photoreceptor cells. Together, these results point to potential novel roles for IDE in retinal physiology and disease, further extending the list of diverse functions attributed to this enzyme.
Although considered a rare retinal dystrophy, retinitis pigmentosa (RP) is the primary cause of hereditary blindness. Given its diverse genetic etiology (>3000 mutations in >60 genes), there is an ...urgent need for novel treatments that target common features of the disease. TLR2 is a key activator of innate immune response. To examine its role in RP progression we characterized the expression profile of
and its adaptor molecules and the consequences of
deletion in two genetically distinct models of RP:
(
) and
(
) mice. In both models, expression levels of
and its adaptor molecules increased in parallel with those of the proinflammatory cytokine
. In
mice, deletion of a single
allele had no effect on visual function, as evaluated by electroretinography. However, in both RP models, complete elimination of
attenuated the loss of visual function and mitigated the loss of photoreceptor cell numbers. In
null
mice, we observed decreases in the total number of microglial cells, assessed by flow cytometry, and in the number of microglia infiltrating the photoreceptor layers. Together, these results point to TLR2 as a mutation-independent therapeutic target for RP.
Synaptic loss, neuronal death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa (RP), the leading cause of inherited blindness, ...is a group of retinal dystrophies characterized by photoreceptor dysfunction and death. The insulin receptor, a key controller of metabolism, also regulates neuronal survival and synaptic formation, maintenance, and activity. Indeed, deficient insulin receptor signaling has been implicated in several brain neurodegenerative pathologies. We present evidence linking impaired insulin receptor signaling with RP. We describe a selective decrease in the levels of the insulin receptor and its downstream effector phospho-S6 in retinal horizontal cell terminals in the rd10 mouse model of RP, as well as aberrant synapses between rod photoreceptors and the postsynaptic terminals of horizontal and bipolar cells. A gene therapy strategy to induce sustained proinsulin, the insulin precursor, production restored retinal insulin receptor signaling, by increasing S6 phosphorylation, without peripheral metabolic consequences. Moreover, proinsulin preserved photoreceptor synaptic connectivity and prolonged visual function in electroretinogram and optomotor tests. These findings point to a disease-modifying role of insulin receptor and support the therapeutic potential of proinsulin in retinitis pigmentosa.
Retinitis pigmentosa (RP) is a group of hereditary retinal neurodegenerative conditions characterized by primary dysfunction and death of photoreceptor cells, resulting in visual loss and, ...eventually, blindness. To date, no effective therapies have been transferred to clinic. Given the diverse genetic etiology of RP, targeting common cellular and molecular retinal alterations has emerged as a potential therapeutic strategy.
Using the Pde6b
mouse model of RP, we investigated the effects of daily intraperitoneal administration of VP3.15, a small-molecule heterocyclic GSK-3 inhibitor. Gene expression was analyzed by quantitative PCR and protein expression and phosphorylation by Western blot. Photoreceptor preservation was evaluated by histological analysis and visual function was assessed by electroretinography.
In rd10 retinas, increased expression of pro-inflammatory markers and reactive gliosis coincided with the early stages of retinal degeneration. Compared with wild-type controls, GSK-3β expression (mRNA and protein) remained unchanged during the retinal degeneration period. However, levels of GSK-3β
and its regulator Akt
were increased in rd10 versus wild-type retinas. In vivo administration of VP3.15 reduced photoreceptor cell loss and preserved visual function. This neuroprotective effect was accompanied by a decrease in the expression of neuroinflammatory markers.
These results provide proof of concept of the therapeutic potential of VP3.15 for the treatment of retinal neurodegenerative conditions in general, and RP in particular.
Retinitis pigmentosa (RP) is a genetically heterogeneous disease and the predominant cause of hereditary blindness. Irrespective of the causative mutation, traits common to all forms of RP include ...photoreceptor dysfunction and death, activation of the retinal glial component, and retinal inflammation. Activation of Toll-like receptors (TLRs) in response to tissue damage is associated with inflammatory processes that contribute to neurodegeneration. We show that retinal expression of the genes Tlr1 to Tlr9 is increased in the rd10 mouse model of RP, with Tlr2 showing the greatest increase (36-fold). Flow cytometry analysis of the retinal myeloid population revealed significant increases in numbers of microglia and infiltrating monocytes and macrophages in rd10 retinas. Furthermore, TLR2 expression, which was restricted to myeloid cells, was increased in rd10 retinal microglia. These observations, together with our previous finding of delayed RP progression following Tlr2 deletion, point to TLR2 as a potential therapeutic target for RP.
PDF
