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- Title
Modulation of GSK-3 provides cellular and functional neuroprotection in the <italic>rd10</italic> mouse model of retinitis pigmentosa.
- Authors
Sánchez-Cruz, Alonso; Villarejo-Zori, Beatriz; Marchena, Miguel; Zaldivar-Díez, Josefa; Palomo, Valle; Gil, Carmen; Lizasoain, Ignacio; de la Villa, Pedro; Martínez, Ana; de la Rosa, Enrique J.; Hernández-Sánchez, Catalina
- Abstract
Background: 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. Methods: Using the <italic>Pde6b</italic><italic>rd10/rd10</italic> 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. Results: In <italic>rd10</italic> 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 <italic>rd10</italic> 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. Conclusions: 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.
- Subjects
RETINITIS pigmentosa; KINASE inhibitors; NEURODEGENERATION; GENE expression; LABORATORY mice; POLYMERASE chain reaction; WESTERN immunoblotting; THERAPEUTICS
- Publication
Molecular Neurodegeneration, 2018, Vol 13, Issue 1, pN.PAG
- ISSN
1750-1326
- Publication type
Article
- DOI
10.1186/s13024-018-0251-y