Retinal Photoreceptor Protection in an AMD-Related Mouse Model by Selective Sigma-1 or Sigma-2 Receptor Modulation.

Autor: Mavlyutov TA; Department of Surgery, University of Wisconsin, Madison, WI 53705, USA., Li J; Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Liu X; Department of Pediatrics, University of Wisconsin, Madison, WI 53705, USA., Shen H; Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Yang H; Department of Surgery, University of Wisconsin, Madison, WI 53705, USA., McCurdy CR; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA., Pattnaik B; Department of Pediatrics, University of Wisconsin, Madison, WI 53705, USA.; Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53705, USA.; McPherson Eye Research Institute, University of Wisconsin, Madison, WI 53705, USA., Guo LW; Department of Surgery, University of Wisconsin, Madison, WI 53705, USA.; Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.; McPherson Eye Research Institute, University of Wisconsin, Madison, WI 53705, USA.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Jazyk: angličtina
Zdroj: Genes [Genes (Basel)] 2022 Dec 16; Vol. 13 (12). Date of Electronic Publication: 2022 Dec 16.
DOI: 10.3390/genes13122386
Abstrakt: The structurally and genetically distinct sigma-1 receptor (S1R) and sigma-2 receptor (S2R) comprise a unique class of drug binding sites. Their alleles are associated with human diseases involving neuronal systems, such as age-related macular degeneration (AMD) characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. Previous studies have suggested neuroprotective benefits for the brain and retina from pharmacological modulation of S1R and/or S2R. However, the effect of such modulation on AMD pathology remains underexplored. Here, we evaluated S1R- or S2R-selective modulation in an AMD-related model of Abca4 -/- Rdh8 -/- mice with a disrupted visual cycle that predisposes RPE and photoreceptors to illumination-induced damage. For S1R modulation, we used (+)-pentazocine, which is a high-affinity S1R-selective drug. For S2R modulation, we chose CM398, a high-affinity and highly S2R-selective ligand with drug-like properties. Abca4 -/- Rdh8 -/- mice received a single i.p. injection of (+)-pentazocine or CM398 or vehicle 30 min before illumination. Pretreatment with (+)-pentazocine improved electroretinogram a- and b-waves compared to that with vehicle. Consistently, in another AMD-related mouse model induced by tail-vein injected NaIO 3 , S1R genetic ablation aggravated photoreceptor loss. In Abca4 -/- Rdh8 -/- mice, pretreatment with CM398 appeared to partially avert illumination-induced photoreceptor loss and autofluorescent granule formation that signals RPE damage, as revealed by optical coherence tomography. Thus, this study using AMD-related models provides evidence of photoreceptor protection afforded by selective modulation of S1R or S2R.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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