Astragaloside A Protects Against Photoreceptor Degeneration in Part Through Suppressing Oxidative Stress and DNA Damage-Induced Necroptosis and Inflammation in the Retina

Photoreceptors are specialized retinal neurons responsible for phototransduction. Loss of photoreceptors directly leads to irreversible vision impairment. Pharmacological therapies protecting against photoreceptor degeneration are clinically lacking. Oxidative stress and inflammation are common mechanisms playing important roles in the pathogenesis of photoreceptor degeneration. Astragaloside A (AS-A) is a naturally occurring antioxidant and anti-inflammatory agent with neuroprotective activities. However, the photoreceptor protective effects of AS-A remain unknown. The current study thus aims to illustrate the pharmacological potentials of AS-A in protecting against photoreceptor degeneration.BALB/c and C57/BL6J mice were exposed to bright light and DNA alkylating agent methyl methanesulfonate (MMS) to develop oxidative stress and DNA damage-mediated photoreceptor degeneration, respectively. Microstructural, morphological and functional assessments were performed to directly evaluate the photoreceptor protective effects of AS-A. Ultrastructural and molecular changes in the retina were examined to better understand the pharmacological mechanisms of AS-A in protecting against photoreceptor degeneration.AS-A protected against bright light-induced photoreceptor impairment. Bright light-induced retinal oxidative stress and photoreceptor cell death were attenuated by AS-A treatment. AS-A treatment mitigated bright light-induced DNA damage, activation of poly (ADP-ribose) polymerase (PARP) and nuclear dislocation of high mobility group box 1 (HMGB1) in photoreceptors. AS-A broadly counteracted bright light-altered retinal gene expression profiles. In particular, AS-A decreased the retinal expression of genes involved in necroptosis and inflammatory responses. Bright light-induced microglial activation was also suppressed as a result of AS-A treatment. Furthermore, AS-A attenuated MMS-induced photoreceptor morphological impairment, elevated expression of pro-necroptotic and proinflammatory genes as well as microglial activation in the retina.The work here demonstrates for the first time that AS-A protects against photoreceptor degeneration in part through mitigating oxidative stress and DNA damage-induced necroptosis and inflammatory responses in the retina.