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

authors

  • SÁNCHEZ CRUZ, ALONSO
  • VILLAREJO-ZORI, BEATRIZ
  • MARCHENA, MIGUEL
  • ZALDIVAR DIEZ DE BONILLA, JOSEFA
  • MARTINEZ FINKELSHTEIN, ANDREI
  • PALOMO, VALLE
  • GIL, CARMEN
  • LIZASOAIN, IGNACIO
  • DE LA VILLA, PEDRO
  • MARTÍNEZ, ANA
  • DE LA ROSA, ENRIQUE J.
  • HERNÁNDEZ-SÁNCHEZ, CATALINA

publication date

  • January 2018

start page

  • 19

volume

  • 13

International Standard Serial Number (ISSN)

  • 1750-1326

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 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.

    Results: 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-3beta expression (mRNA and protein) remained unchanged during the retinal degeneration period. However, levels of GSK-3betaSer9 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.

    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

  • Biology and Biomedicine

keywords

  • gsk-3; retina; retinitis pigmentosa; rd10; neurodegeneration; therapy