BackgroundRetinitis 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.MethodsUsing the Pde6brd10/rd10 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.ResultsIn 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-3βSer9 and its regulator AktSer473 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0251-y) contains supplementary material, which is available to authorized users.
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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 Tlr2 and its adaptor molecules and the consequences of Tlr2 deletion in two genetically distinct models of RP: Pde6brd10/rd10 (rd10) and RhoP23H/+ (P23H/+) mice. In both models, expression levels of Tlr2 and its adaptor molecules increased in parallel with those of the proinflammatory cytokine Il1b. In rd10 mice, deletion of a single Tlr2 allele had no effect on visual function, as evaluated by electroretinography. However, in both RP models, complete elimination of Tlr2 attenuated the loss of visual function and mitigated the loss of photoreceptor cell numbers. In Tlr2 null rd10 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.
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