Journal Article

Hybrid molecule SA-10 and its PLGA nanosuspension protect human and rodent retinal ganglion cells against neuronal injury

Sinnott, Ella R., Acharya, Suchismita, Zhang, Wei, Pham, Jennifer H., Bui, Thien T., Johnson, Gretchen A., Krishnamoorthy, Raghu R., Gitter, Rachel Y., Gutierrez, Jonah P., Hatfield, Brendon R., Satyal, Rojan, Stankowska, Dorota L., DebNath, Biddut, Le, Kim-Tuyen T., Kodati, Bindu, Amankwa, Charles E.

2025

Overview

Background Glaucoma is a leading cause of blindness characterized by retinal ganglion cell (RGC) degeneration. SA-10, a dual-acting compound with ROS scavenging and NO-donating properties, was evaluated to enhance RGC survival and function in models of oxidative stress, ischemia/reperfusion (I/R) injury, and neurotrophic factor (NF) deprivation. Methods SA-10-loaded nanoparticles (SA-10-NP) with a size of 279.6 ± 20.9 nm, polydispersity index of 0.34, and encapsulation efficiency of 80.6% were synthesized and tested for sustained release over 28 days. I/R injury was induced by elevating intraocular pressure to 120 mmHg for 60 min in C57BL/6J mice, followed by SA-10-NP treatment (1% w/v). Retinal ganglion cell function and survival were evaluated using PERG and PVEP. Oxidative stress in primary RGCs and retinal explants was induced using endothelin-3 (ET-3), and the effects of SA-10 (10 µM) on ROS levels were assessed. In ex vivo human retinal explants (HREs), SA-10 treatment effects on oxidative stress markers NRF2 and HMOX1 were analyzed. Results SA-10-NP improved PERG amplitudes (112.96% in females, p  < 0.01) and PVEP amplitudes (67.53% in females, p  < 0.01), preserving RGC density in both central and mid-peripheral regions. Immunohistochemistry showed upregulation of Hmox1 and downregulation of TNF-α in the SA-10-NP-treated group. SA-10 significantly reduced ROS levels in primary RGCs and retinal explants exposed to endothelin-3 (ET-3), decreasing fluorescence intensity by 25.9% ( p  < 0.01) and 14.7% ( p  < 0.0001), respectively. SA-10 upregulated oxidative stress markers (NRF2 and HMOX1) and enhanced RGC survival in NF-deprived HREs. Conclusions SA-10 demonstrated significant ROS reduction and preserved RGC survival and function in both I/R mouse models and HREs, with immunohistochemistry confirming upregulation of Hmox1 and downregulation of TNF-α in the SA-10-NP-treated group. SA-10-NP provided sustained drug delivery and bioavailability, showcasing strong neuroprotective effects and offering a potential therapeutic strategy for glaucomatous optic neuropathy and other neurodegenerative conditions.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animal Models / Animals / Antioxidants / Bioavailability / Biodistribution / Biomedical and Life Sciences / Biomedicine / Biomolecules / Cell survival / Cell Survival - drug effects / Cells, Cultured / Chromatography / Controlled release / Down-regulation / Drug delivery / Drug delivery systems / Drug dosages / Drug therapy / Drugs / Efficiency / Endothelin 3 / Explants / Glaucoma / Glaucoma - drug therapy / Health aspects / Humans / Hypoxia / Immunohistochemistry / Ischemia / Laboratories / Male / Mice / Mice, Inbred C57BL / Nanoparticles / Nanoparticles - administration & dosage / Neurobiology / Neurodegeneration / Neuroprotection / Neuroprotective Agents - administration & dosage / Neuroprotective Agents - pharmacology / Neurosciences / Neurotrophic factors / Optic neuropathy / Oxidative stress / Oxidative Stress - drug effects / Peripheral neuropathy / Pharmaceutical research / Polylactic Acid-Polyglycolic Acid Copolymer / Polylactide-co-glycolide / Postpartum period / Reactive oxygen species / Reactive Oxygen Species - metabolism / Reperfusion / Reperfusion Injury - drug therapy / Retina / Retinal ganglion cells / Retinal Ganglion Cells - drug effects / Retinal Ganglion Cells - metabolism / Retinal Ganglion Cells - pathology / Spectrum analysis / Tumor necrosis factor-α / Up-regulation / Vehicles