PMID- 33310057 OWN - NLM STAT- MEDLINE DCOM- 20210426 LR - 20231213 IS - 1096-0007 (Electronic) IS - 0014-4835 (Print) IS - 0014-4835 (Linking) VI - 202 DP - 2021 Jan TI - Optimal timing for activation of sigma 1 receptor in the Pde6b(rd10)/J (rd10) mouse model of retinitis pigmentosa. PG - 108397 LID - S0014-4835(20)30655-2 [pii] LID - 10.1016/j.exer.2020.108397 [doi] AB - Sigma 1 Receptor (Sig1R), a pluripotent modulator of cell survival, is a promising target for treatment of retinal degenerative diseases. Previously, we reported that administration of the high-affinity, high-specificity Sig1R ligand (+)-pentazocine, ((+)-PTZ) beginning at post-natal day 14 (P14) and continuing every other day improves visual acuity and delays loss of photoreceptor cells (PRCs) in the Pde6betard10/J (rd10) mouse model of retinitis pigmentosa. Whether administration of (+)-PTZ, at time points concomitant with (P18) or following (P21, P24) onset of PRC death, would prove neuroprotective was investigated in this study. Rd10 mice were administered (+)-PTZ intraperitoneally [0.5 mg/kg], starting at either P14, P18, P21 or P24. Injections continued every other day through P42. Visual acuity was assessed using the optokinetic tracking response (OKR). Rd10 mice treated with (+)-PTZ beginning at P14 retained visual acuity for the duration of the study (~0.33 c/d at P21, ~0.38 c/d at P28, ~0.32 c/d at P35, ~0.32 c/d at P42), whereas mice injected beginning at P18, P21, P24 showed a decline in acuity when tested at P35 and P42. Their acuity was only slightly better than rd10-non-treated mice. Electrophysiologic function was assessed using scotopic and photopic electroretinography (ERG) to assess rod and cone function, respectively. Photopic a- and b-wave amplitudes were significantly greater in rd10 mice treated with (+)-PTZ beginning at P14 compared with non-treated mice and those in the later-onset (+)-PTZ injection groups. Retinal architecture was visualized in living mice using spectral domain-optical coherence tomography (SD-OCT) allowing measurement of the total retinal thickness, the inner retina and the outer retina (the area most affected in rd10 mice). The outer retina measured ~35 mum in rd10 mice treated with (+)-PTZ beginning at P14, which was significantly greater than mice in the later-onset (+)-PTZ injection groups (~25 mum) and non-treated rd10 mice (~25 mum). Following the visual function studies performed in the living mice, eyes were harvested at P42 for histologic analysis. While the inner retina was largely intact in all (+)-PTZ-injection groups, there was a marked reduction in the outer retina of non-treated rd10 mice (e.g. in the outer nuclear layer there were ~10 PRCs/100 mum retinal length). The rd10 mice treated with (+)-PTZ beginning at P14 had ~20 PRCs/100 mum retinal length, whereas the mice in groups beginning P18, P21 and P24 had ~16 PRCs/100 mum retinal length. In conclusion, the data indicate that delaying (+)-PTZ injection past the onset of PRC death in rd10 mice - even by a few days - can negatively impact the long-term preservation of retinal function. Our findings suggest that optimizing the administration of Sig1R ligands is critical for retinal neuroprotection. CI - Copyright (c) 2020. Published by Elsevier Ltd. FAU - Wang, Jing AU - Wang J AD - Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States. FAU - Xiao, Haiyan AU - Xiao H AD - Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States. FAU - Barwick, Shannon AU - Barwick S AD - Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States. FAU - Liu, Yutao AU - Liu Y AD - Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States. FAU - Smith, Sylvia B AU - Smith SB AD - Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States; Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, United States. Electronic address: sbsmith@augusta.edu. LA - eng GR - P30 EY031631/EY/NEI NIH HHS/United States GR - R01 EY023242/EY/NEI NIH HHS/United States GR - R01 EY028103/EY/NEI NIH HHS/United States GR - R21 EY028671/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201209 PL - England TA - Exp Eye Res JT - Experimental eye research JID - 0370707 RN - 0 (Receptors, sigma) RN - EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 6) RN - EC 3.1.4.35 (Pde6b protein, mouse) SB - IM MH - Animals MH - Cyclic Nucleotide Phosphodiesterases, Type 6/*metabolism MH - Disease Models, Animal MH - Electroretinography MH - Mice MH - Mice, Inbred C57BL MH - Receptors, sigma/*metabolism MH - Retinal Cone Photoreceptor Cells/*metabolism/pathology MH - Retinal Rod Photoreceptor Cells/*metabolism/pathology MH - Retinitis Pigmentosa/*metabolism/pathology MH - Tomography, Optical Coherence MH - Sigma-1 Receptor PMC - PMC7808329 MID - NIHMS1657010 OTO - NOTNLM OT - ERG OT - OCT OT - Pentazocine OT - Retinal degeneration OT - Retinitis pigmentosa OT - Sigma 1 receptor OT - optomotry OT - rd10 mouse EDAT- 2020/12/15 06:00 MHDA- 2021/04/27 06:00 PMCR- 2022/01/01 CRDT- 2020/12/14 10:19 PHST- 2020/10/09 00:00 [received] PHST- 2020/11/24 00:00 [revised] PHST- 2020/12/07 00:00 [accepted] PHST- 2020/12/15 06:00 [pubmed] PHST- 2021/04/27 06:00 [medline] PHST- 2020/12/14 10:19 [entrez] PHST- 2022/01/01 00:00 [pmc-release] AID - S0014-4835(20)30655-2 [pii] AID - 10.1016/j.exer.2020.108397 [doi] PST - ppublish SO - Exp Eye Res. 2021 Jan;202:108397. doi: 10.1016/j.exer.2020.108397. Epub 2020 Dec 9.