Abstract
Purpose :
Activation of Sig1R using the high affinity ligand (+)-pentazocine ((+)-PTZ) rescues cone photoreceptors in the Pde6brd10/J (rd10) mouse model of RP, however dissecting cellular mechanisms of rescue is challenging due to the rapid pathology of the model. The knock-in RhoP23H/+ mouse progresses more slowly, mimicking the pathological progression of human adRP, thus allowing study of cell biological mechanisms of disease & therapeutic strategies. Here we evaluate retinal architecture & visual acuity when Sig1R is activated in RhoP23H/+ mice.
Methods :
3 groups of mice were used: C57BL/6 (WT) (n=34), RhoP23H/+ (n=28), (+)-PTZ-injected RhoP23H/+ (n=54). (+)-PTZ (0.5 mg/kg, intraperitoneally 3X/wk) was administered at P14 & continued through P180. Longitudinal studies were performed to evaluate retinal architecture & visual acuity using optical coherence tomography (OCT) & optokinetic response (OKR), respectively. For OCT, averaged single B-scan/volume intensity scans centered on the optic nerve head were evaluated using the manual caliper function to measure inner/outer retinal thickness. Spatial thresholds for optokinetic tracking of sine-wave gratings were measured using the OptoMotry system and expressed as cycles/degree (c/d). Data were analyzed by two-way ANOVA (p>0.05).
Results :
Retinal architecture (OCT): RhoP23H/+ mice have markedly decreased outer retinal thickness (ORT). ORT in WT was 135.5±0.44μm at P180; it was 46.7±0.57μm for non-injected RhoP23H/+ mice. ORT in age-matched (+)-PTZ-injected RhoP23H/+ mice was significantly greater than non-injected (52.4 ±0.65μm, p<0.0001). Visual acuity (OKR): At P180, visual acuity in WT mice was 0.408 ± 0.002 c/d; in non-injected RhoP23H/+ mice it was significantly less (0.350 ± 0.008 c/d (p<0.0001). The OKR for (+)-PTZ-injected RhoP23H/+ mice was 0.384 ± 0.004 c/d, which was significantly greater than non-injected mutants (p=0.0001); it did not differ significantly from WT.
Conclusions :
Activation of Sig1R was associated with improved retinal architecture & visual acuity in RhoP23H/+ mice, a highly relevant model of adRP. These in vivo studies are promising & set the stage to evaluate comprehensively whether the formation of rod outer segment disks & cone responsiveness (known to be disrupted in the RhoP23H/+ mouse) are rescued by (+)-PTZ treatment.
This is a 2020 ARVO Annual Meeting abstract.