September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Sirt1 activators induced neuroprotection of photoreceptors in rd10 mice
Author Affiliations & Notes
  • Francisco Javier Diaz-Corrales
    Cell Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, Andalusia, Spain
  • Juan Carlos Morales-Sánchez
    Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine "López-Neyra", Granada, Andalusia, Spain
  • Lourdes Valdés-Sánchez
    Cell Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, Andalusia, Spain
  • Ricardo Lucas-Rodríguez
    Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine "López-Neyra", Granada, Andalusia, Spain
  • Daniel Rodriguez-Martinez
    Cell Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, Andalusia, Spain
  • Pablo Peñalver
    Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine "López-Neyra", Granada, Andalusia, Spain
  • Andrea Diez-Lloret
    Cell Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, Andalusia, Spain
  • Vaibhav Bhatia
    Cell Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, Andalusia, Spain
  • Berta De la Cerda
    Cell Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, Andalusia, Spain
  • Eduardo Rodriguez-Bocanegra
    Cell Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, Andalusia, Spain
  • Shomi S Bhattacharya
    Cell Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, Andalusia, Spain
  • Footnotes
    Commercial Relationships   Francisco Diaz-Corrales, None; Juan Morales-Sánchez , None; Lourdes Valdés-Sánchez , None; Ricardo Lucas-Rodríguez, None; Daniel Rodriguez-Martinez, None; Pablo Peñalver, None; Andrea Diez-Lloret, None; Vaibhav Bhatia, None; Berta De la Cerda, None; Eduardo Rodriguez-Bocanegra, None; Shomi Bhattacharya, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4388. doi:
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      Francisco Javier Diaz-Corrales, Juan Carlos Morales-Sánchez, Lourdes Valdés-Sánchez, Ricardo Lucas-Rodríguez, Daniel Rodriguez-Martinez, Pablo Peñalver, Andrea Diez-Lloret, Vaibhav Bhatia, Berta De la Cerda, Eduardo Rodriguez-Bocanegra, Shomi S Bhattacharya; Sirt1 activators induced neuroprotection of photoreceptors in rd10 mice. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4388.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : It has been reported that Sirt1 nuclear expression decreases in the outer nuclear layer (ONL) of retinal degeneration 10 (rd10) mice at postnatal day 15 (P15), and this abnormal pattern is correlated with the beginning of photoreceptor degeneration. Sirt1 is a class III histone deacetylase, and over-expression of these proteins have shown neuroprotective effect in several experimental models of neurodegenerative diseases. However, it is still unknown whether Sirt1 modulation could induce neuroprotection of photoreceptors. We tested the hypothesis that subretinal injection of new Sirt1 activators would slow degeneration of photoreceptors using an experimental mouse model of autosomal recessive retinitis pigmentosa (RP).

Methods : A library of resveratrol derivatives were newly synthesized in order to improve the solubility and bioavailability of this lead compound. The new optimized Sirt1 activators were tested for preclinical drug development. Rd10 mice (P13) were subretinal injected with 1 µL of vehicle, resveratrol or several new Sirt1 activators. Electroretinogram (ERG), fundus, and histological evaluation were performed 15 days after injections. Amplitude of a- and b-waves were quantified in ERG recordings, and the statistical analyses were calculated by one-way ANOVA and post hoc DMS. A p value < 0.05 was considered significant.

Results : Fundus evaluation showed less amount of pigment patches in both JC19 and JC21 treated mouse retinas when compared with non-treated and vehicle treated rd10 mice (controls). In addition, the number of photoreceptors nuclei in the ONL and the immunostaining of rhodopsin were preserved in JC19 and JC21 treated mice. b-Wave amplitude in dark-adapted ERG (flash intensities of 0.2, 1, 3 and 10 cd x s/m2) significantly increased in JC21 treated mice when compared with controls. b-Wave amplitude also increased in resveratrol and JC19 treated groups but in a lesser extent. The amplitude of b-wave in dark-adapted ERG-10 was: non-treated=68.4 ± 6.7 µV, vehicle=79.3 ± 10.3 µV, resveratrol= 103.8 ± 12.1 µV (p < 0.05), JC19=110.3 ± 12.5 µV (p < 0.05), JC21= 129.8 ± 27.7 µV (p < 0.01). a-Wave amplitude also showed statistically significant differences in Sirt1 activators treated mice.

Conclusions : Our results are consistent with our hypothesis that Sirt1 activators induce neuroprotection of photoreceptors in a mouse model of RP. Other retinal diseases could be potentially treated with these drugs.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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