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Jing Wang, Haiyan Xiao, Zhimin Xu, Ruth B Caldwell, Sylvia B Smith; Sigma 1 Receptor (Sig1R) activation: a novel therapy for neurovascular injury in Retinopathy of Prematurity (ROP). Invest. Ophthalmol. Vis. Sci. 2020;61(7):5411.
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© ARVO (1962-2015); The Authors (2016-present)
ROP is the most significant cause of childhood blindness. Current clinical standard-of-care (laser photocoagulation or anti-VEGF therapy) targets abnormal retinal angiogenesis. Many children suffer visual impairment, however, due to deficits in retinal neurons even after standard ROP therapy. We reported recently that activation of Sig1R affords profound rescue of cone photoreceptor (PRC) function in Pde6brd10 mice (Wang et al, PNAS, 2016). The relationship of Sig1R and ROP, however, has not been studied. Here we focus on Sig1R and its therapeutic potential in neurovascular injury characteristic of ROP.
C57BL/6J pups (P7 with nursing dam) were subjected to oxygen-induced retinopathy (OIR), a common model of ROP or to room air (CT). (+)-Pentazocine ((+)-PTZ), a high affinity Sig1R ligand, was administered P7-P48 (0.5 mg/kg, IP, every other day). Retinal vasculature was imaged by fluorescein angiography & arterial integrity, including tortuosity, was analyzed using MATLAB. Retinal function/structure was determined as the optokinetic response (OKR), electroretinography (ERG) and spectral domain-optical coherence tomography (SD-OCT).
Vascular analysis: Retinal arteries in OIR mice were significantly more tortuous (~1.3) v. CT (1.0), whereas (+)-PTZ significantly reduced arterial tortuosity (~1.1) in OIR mice at P17 & P48. Neuronal analysis: 1) OKR: OIR mice had reduced visual acuity: P21: ~0.20c/d, P28: ~0.28c/d, P35: ~0.30c/d (v. 0.40c/d in CT at all ages). OIR+PTZ mice showed significantly improved visual acuity: P21: ~0.28c/d, P28: ~0.38c/d, P35: ~0.38c/d. 2) ERG: Scotopic ERG responses were significantly reduced in OIR mice v. CT at P37, whereas responses were improved in PTZ-OIR mice; notably amplitude of scotopic a waves was similar between OIR-PTZ and CT mice. 3) OCT: At P48, compared to CT, OIR mice had significantly decreased thickness of whole retina (WR): 185.5±5.6 v. 221.1±3.7 µm, inner plexiform layer (IPL): 21.0±4.9 v. 52.6±3.3 µm, outer nuclear layer/inner segments: 60.9±6.2 v. 79.2±2.6 µm. OIR+PTZ mice had significantly increased WR: 204.9±2.8 µm, IPL: 30.8±3.9 µm, & ONL/IS: 73.1±1.4 µm.
(+)-PTZ treatment of OIR mice improved vascular structure, visual acuity, electrophysiological responses and in vivo architecture suggesting Sig1R activation is a promising, novel therapy for ROP.
This is a 2020 ARVO Annual Meeting abstract.
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