Wedelolactone Attenuates N-methyl-N-nitrosourea-Induced Retinal Neurodegeneration through Suppression of the AIM2/CASP11 Pathway.

N-methyl-N-nitrosourea (NMU) is widely used to model oxidative stress and inflammation mediated retinal neurodegeneration. Wedelolactone (WD) is known to have antioxidant, anti-inflammatory, and neuroprotective roles. This study tested the therapeutic potential of WD in NMU-induced retinal neurodegeneration and investigated the underlying mechanisms in mice. NMU (40 mg/kg) was injected intraperitoneally into C57BL/6J mice with/without an intravitreal injection of WD (1 μL/eye, 200 μM). Seven days later, retinal function and structure were evaluated by electroretinography (ERG) and Spectral Domain Optical Coherence Tomography (SD-OCT). The expression of inflammasome components ( Aim2 , Caspase 1/11 , and Il1b/Il18 ) in the total retina lysate was evaluated by RT-qPCR. In vitro, 661W photoreceptor cells were transfected with synthetic double-strand DNA (Poly(dA:dT)) with/without WD pre-incubation. The aim2-related inflammasome expression was evaluated by RT-qPCR and immunocytochemistry. The production of IL18 was measured by ELISA. NMU treatment significantly impaired A- and B-wave response (ERG) and reduced neuroretina thickness (OCT). This was significantly attenuated upon intravitreal injection of WD. The expression of Aim2 , ACasp1 , and Casp11 was increased in the retina from NMU-treated mice, and this was prevented by WD treatment. Transfection of Poly(dA:dT) upregulated Aim2, Casp11, and Il18 expression in 661W cells. WD prevented their upregulation and reduced IL18 production. Aim2 inflammasome activation is critically involved in NMU-induced retinal neurodegeneration and WD can protect the retina particularly through the suppression of this inflammasome-linked pathway.