MDL800, a SIRT6 activator, mitigates neuroinflammation-induced retinal damage by modulating microglial M1/M2...

Glaucoma is a group of irreversible neurodegenerative disorders of the optic nerve, characterized by distinct optic nerve damage and progressive visual field loss, with its pathological foundation involving the apoptosis of retinal ganglion cells (RGCs) and axonal degeneration. Neuroinflammation driven by the polarization of retinal microglia significantly contributes to RGCs apoptosis. This study investigates the neuroprotective effects of the SIRT6 activator MDL800 on microglial polarization in experimental glaucoma.

We used a lipopolysaccharide (LPS)-induced BV2 microglial inflammation model and an ocular hypertension (OHT) rat model. The regulatory effects of MDL800 on BV2 cell M1/M2 polarization were evaluated. After inhibiting SIRT6, MDL800's impact on MAPK and AMPK-Nrf2-HO-1/NQO-1 pathways was studied. A co-culture system of BV2 cells and retinal precursor cells R28 was established to observe the effect of MDL800-regulated BV2 cell polarization on R28 cell survival. In the rat model, the effects of MDL800 on microglial polarization, retinal structure, and RGCs apoptosis in glaucoma were assessed.

MDL800 facilitated BV2 cell polarization from M1 to M2 under LPS stimulation, exerting anti-inflammatory effects. It activated SIRT6 to regulate BV2 cell polarization by inhibiting the MAPK pathway and activating the AMPK-Nrf2-HO-1/NQO-1 axis. In a co-culture system of BV2 cells and R28 cells, MDL800 regulated the release of LPS-induced inflammatory factors by mediating the polarization of BV2 cells, which in turn inhibited the mitochondrial apoptotic pathway in R28 cells and promoted their survival. In the OHT rat model, MDL800 significantly inhibited retinal microglia proliferation and activation, promoted their polarization from M1 to M2, and reduced RGCs apoptosis.

MDL800 shows promise for clinical development and treatment of glaucoma.