Sigma1 Receptor Activation Confers Durable Neuroprotection Following Neonatal Ischemic Retinal Injury

Retinopathy of prematurity (ROP) remains a leading cause of childhood blindness. Although current therapies effectively suppress pathological neovascularization, many patients continue to exhibit persistent visual dysfunction despite regression of active disease, highlighting an unmet need for neuroprotective interventions. Sigma 1 receptor (Sig1R), an endoplasmic reticulum-mitochondrial chaperone and regulator of cellular stress responses, has emerged as a promising therapeutic target in neurodegenerative and retinal diseases. Here, we investigated whether Sig1R activation confers sustained neuroprotection following neonatal ischemic retinal injury. Wild-type and Sig1R knockout mice were subjected to oxygen-induced retinopathy (OIR) and treated systemically with the high-affinity Sig1R agonist (+)-pentazocine [(+)-PTZ]. Retinal structure and visual function were assessed longitudinally through 20 weeks of age using visual acuity, contrast sensitivity, electroretinography (ERG), pattern ERG (PERG), spectral-domain optical coherence tomography (SD-OCT), and histological analyses. Chronic Sig1R activation significantly preserved visual acuity, contrast sensitivity, rod- and ganglion cell-mediated retinal function, retinal ganglion cell survival, and inner retinal architecture in OIR mice. These protective effects were abolished in Sig1R-deficient mice, demonstrating a requirement for Sig1R in mediating neuroprotection. Mechanistically, Sig1R activation reduced apoptotic signaling, attenuated oxidative and nitrosative stress, improved mitochondrial respiratory function, and enhanced endogenous antioxidant pathways. Collectively, these findings demonstrate that Sig1R activation provides durable, receptor-dependent neuroprotection following neonatal ischemic retinal injury by coordinating redox, mitochondrial, and cell-survival pathways. These results identify Sig1R as a promising therapeutic target for preserving retinal neuronal integrity and long-term visual function in retinopathy of prematurity.