TSPO Modulation by PIGA-1138 Attenuates Oxidative Stress and Preserves Retinal Function in Experimental Diabetic Retinopathy

Introduction: Diabetic retinopathy (DR) is characterized by early retinal neurodegeneration accompanied by progressive alterations of the retinal microvasculature, both exacerbated by hyperglycemia-induced oxidative stress and inflammation. Mitochondrial dysfunction critically contributes to neuronal loss and vascular impairment. The 18 kDa Translocator Protein (TSPO) is a mitochondrial outer membrane protein whose expression is increased in activated retinal glial cells and represents a promising target to modulate neuroinflammation and oxidative stress. This study evaluates the therapeutic potential of the TSPO ligand PIGA-1138 in experimental models of DR. Methods: PIGA-1138 (3 µM in vitro; 10 mg/kg/day, i.p., in vivo) was evaluated in high glucose (HG)-exposed 661W retinal cells and in streptozotocin (STZ, 150 mg/kg)-induced diabetic C57BL/6J mice. Cell viability, mitochondrial function, oxidative stress, and Nrf2, HO-1, and SOD1 expression were assessed in vitro. Retinal function and morphology were evaluated in vivo by electroretinography (ERG), visual acuity testing, and optical coherence tomography (OCT) at 30 and 60 days after diabetes induction. Results: PIGA-1138 significantly improved cell viability, reducing apoptosis (TUNEL p ≤ 0.01), preserving mitochondrial membrane potential (MitoRed p ≤ 0.01), reducing oxidative damage, and enhancing Nrf2 nuclear translocation together with HO-1 (p ≤ 0.05) and SOD1 (p ≤ 0.01) expression in HG-treated retinal cells. In diabetic mice, treatment preserved ERG responses and limited retinal thinning at 60 days (p ≤ 0.01), while showing a trend toward preserving visual acuity. Conclusions: Targeting mitochondrial TSPO with PIGA-1138 attenuates key hallmarks of DR by mitigating oxidative stress, suppressing neuroinflammation, and preserving retinal structure and function. These findings support TSPO as a potential disease-modifying target for DR.