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

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

  • Genes (Basel). 2022 Dec 16;13(12):2386. doi: 10.3390/genes13122386.
Timur A Mavlyutov 1,  Jing Li 2,  Xinying Liu 3,  Hongtao Shen 2,  Huan Yang 1,  Christopher R McCurdy 4,  Bikash Pattnaik 3 5 6,  Lian-Wang Guo 1 2 6 7
Affiliations

Affiliations

  • 1 Department of Surgery, University of Wisconsin, Madison, WI 53705, USA.
  • 2 Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
  • 3 Department of Pediatrics, University of Wisconsin, Madison, WI 53705, USA.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
  • 5 Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53705, USA.
  • 6 McPherson Eye Research Institute, University of Wisconsin, Madison, WI 53705, USA.
  • 7 Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
PMID: 36553653 DOI: 10.3390/genes13122386
Abstract

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 NaIO3, 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.

Keywords

AMD-related model; photoreceptor protection; retinal pigment epithelium; selective ligands; sigma-1 and sigma-2 receptors.

Figures
Products