Astaxanthin protects retinal Müller cells against high glucose-induced oxidative stress through the sirtuin...

Diabetic retinopathy (DR) is characterized by microvascular damage in the retina due to hyperglycemia-induced oxidative stress. The pivotal role of Müller glial cells in DR pathogenesis has gained increasing recognition. Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase, plays a crucial role in DR by preventing mitochondrial damage and apoptosis. Astaxanthin has protective effects against various diseases with its antioxidant and anti-inflammatory potency, but its interaction with SIRT1 in DR has not been explored. We hypothesized that astaxanthin alleviates high glucose (HG)-induced oxidative stress in Müller cells by activating SIRT1. To test this, rat retinal Müller cells (rMC-1 cells) were exposed to various concentrations of astaxanthin under HG conditions. The effects of astaxanthin on oxidative stress and glial proliferation were evaluated by immunohistochemistry and Western blotting. The molecular pathway linking astaxanthin to SIRT1 was explored using specific inhibitors and siRNAs. Under HG conditions, astaxanthin effectively reduced reactive oxygen species (ROS) levels, restored glutathione levels, and preserved mitochondrial function in rMC-1 cells. Astaxanthin also inhibited HG-induced glial activation, as indicated by reduced glial fibrillary acidic protein (GFAP) expression. SIRT1 inhibition attenuated these protective effects, suggesting the involvement of the SIRT1 pathway. Additionally, astaxanthin upregulated AMP-activated protein kinase (AMPK), restoring intracellular NAD⁺ levels and enhancing SIRT1 activity. Furthermore, astaxanthin promoted SIRT1-mediated deacetylation of forkhead box O1 (FOXO1), a direct substrate of SIRT1, inhibiting oxidative stress and glial activation. This study provides insights into the molecular mechanisms by which astaxanthin protects against DR by activating the SIRT1/AMPK/FOXO1 pathway.