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

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.

Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases

“…While ongoing studies attempt to elucidate the functions of each protein, S2R, TMEM97, and PGRMC1 converge in co-localization/co-expression and their regulation of amyloid-β binding. References: (1) [ 80 , 81 ]; (2) [ 82 ]; (3) [ 5 , 63 , 67 , 73 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ]; (4) [ 62 , 66 ]; (5) [ 51 , 91 , 92 ]; (6) [ 16 , 61 ]; (7) [ 61 , 93 , 94 ]; (8) [ 1 , 59 , 95 ]; (9) [ 2 , 3 , 96 ]; (10) [ 97 , 98 , 99 ]; (11) [ 100 ]; (12) [ 78 ]; (13) [ 101 , 102 ]; (14) [ 103 , 104 , 105 , 106 ] Abbreviations: Aβ, amyloid-β; Apo-E, apolipoprotein-E; BDNF, brain-derived neurotrophic factor; DTG, di-o-tolylguanidine; EGFR, epidermal growth factor receptor; GLP-1R, glucagon-like peptide-1 receptor; Insig/Scap, insulin-induced gene/sterol regulatory element-binding protein cleavage-activating protein; LDLR, low-density lipoprotein receptor; MAP1LC3/UVRAG, microtubule-associated proteins 1A/1B light chain 3/UV radiation resistance associated gene protein; mPRα, membrane progesterone receptor alpha; NPC1, Niemann–Pick protein C1; PAIRBP, plasminogen activator inhibitor 1 mRNA-binding protein; PGRMC1, progesterone receptor membrane component 1; S2R, sigma-2 receptor; TME...…”

“…Either TMEM97 knockout or the S2R-selective modulator DKR-1677 provided neuroprotection against ischemia-induced murine retinal ganglion cell degeneration [ 73 ]. Furthermore, using an illumination-induced degeneration model of AMD in Abca/Rdh8-null mice, S2R-selective modulation using CM398 reduced photoreceptor loss and accumulation of retinal autofluorescent granules, a marker of retinal pigment epithelium cell degeneration [ 84 ]. Taken together, these data indicate that S2R function is important in dry AMD pathogenesis and in other retinopathies.…”