Sirt1 activators induced neuroprotection of photoreceptors in rd10 mice

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.