Modulation of GSK-3 provides cellular and functional neuroprotection in the rd10 mouse model of retinitis pigmentosa

Alonso Sánchez-Cruz,Carmen Gil,Ignacio Lizasoain,Miguel Marchena,Ana Martínez,Catalina Hernández-Sánchez,Enrique J De La Rosa,Valle Palomo,Beatriz Villarejo-Zori,Pedro De La Villa,Josefa Zaldivar-Díez

doi:10.1186/s13024-018-0251-y

Abstract

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.

Highlights

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
Inflammatory genes are upregulated in rd10 mice during the early stages of retinal neurodegeneration Pathological neuroinflammation is a hallmark of neurodegeneration in many retinal dystrophies [2,3,4,5]
We measured the expression of total Glycogen synthase kinase (GSK)-3β and of its inactive Ser9phosphorylated form (GSK-3βSer9) in rd10 mouse retinas

Summary

Introduction

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. Inherited retinal dystrophies, which include retinitis pigmentosa (RP), are a group of genetic diseases caused by mutations in over 300 genes and loci RP is a retinal neurodegenerative condition characterized by primary dysfunction and death of photoreceptor cells, resulting in vision loss and, blindness [1]. Targeting common cellular and molecular retinal responses to mutations could benefit a significant number of RP patients, as well as those with other retinal dystrophies without an exclusively genetic etiology (e.g., glaucoma, age-related macular degeneration, diabetic retinopathy). Recent studies suggest that retinal neurodegeneration is associated with a broad inflammatory response in the retina This response appears to be mutation-independent and involves

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