DAla2-GIP-Glu-PAL exerts neuroprotective effect on diabetic retinopathy by attenuating microglia activation and regulating NF-κB/NLRP3 and Nrf2/HO-1 pathways

DAla2-GIP-Glu-PAL, a kind of analogue of glucose-dependent insulinotropic polypeptide (GIP), has neuroprotective effects in the central nervous system. Currently, retinal neurodegeneration is regarded as an important feature of diabetic retinopathy (DR). The objective of this study was to investigate the neuroprotective effect of DAla2-GIP-Glu-PAL on diabetic retinopathy (DR), and its possible mechanisms, including regulation of microglia activation, inflammatory response, and oxidative stress. In this study, Type 2 diabetic db/db mice and wild-type (WT) mice were used. The morphology and structure of the retina and the ganglion cell layer were observed using histological methods. The levels of PSD95, IL-1β, IL-18, pNrf2, HO-1, MDA, SOD, NF-κBp65, NLRP3, Cleaved-Caspase-1, and GSDMD were detected to evaluate retinal oxidative stress and neuroinflammation, and to observe the changes in levels of these indicators after the intravitreal injection of DAla2-GIP-Glu-PAL. The findings demonstrated that db/db mice exhibited significant retinal pathological changes, loss of ganglion cells, decreased synaptic transmission function, and excessive activation of microglia. In addition, the levels of NF-κBp65, NLRP3, Cleaved-Caspase-1, GSDMD, L-1β, IL-18, and MDA increased, while the levels of pNrf2, HO-1, and SOD decreased. DAla2-GIP-Glu-PAL reversed the excessive activation of microglia and the expression of indicators related to inflammatory responses and oxidative stress, promoting the recovery of retinal neural structure and function.These results imply that DAla2-GIP-Glu-PAL exerted a neuroprotective effect on diabetic retinopathy in mice by inhibiting excessive activation of microglia, inflammatory response, and oxidative stress. Its underlying mechanisms may involve downregulating the NF-κB/NLRP3 pathway and upregulating the Nrf2/HO-1 pathway.