Wolfberry‐derived zeaxanthin dipalmitate delays retinal degeneration in a mouse model of retinitis pigmentosa through modulating STAT3, CCL2 and MAPK pathways

Retinitis pigmentosa (RP) is a group of inherited photoreceptor degeneration diseases that causes blindness without effective treatment. The pathogenesis of retinal degeneration involves mainly oxidative stress and inflammatory responses. Zeaxanthin dipalmitate (ZD), a wolfberry‐derived carotenoid, has anti‐inflammatory and anti‐oxidative stress effects. Here we investigated whether these properties of ZD can delay the retinal degeneration in rd10 mice, a model of RP, and explored its underlying mechanism. One shot of ZD or control vehicle was intravitreally injected into rd10 mice on postnatal day 16 (P16). Retinal function and structure of rd10 mice were assessed at P25, when rods degenerate substantially, using a visual behavior test, multi‐electrode‐array recordings and immunostaining. Retinal pathogenic gene expression and regulation of signaling pathways by ZD were explored using transcriptome sequencing and western blotting. Our results showed that ZD treatment improved the visual behavior of rd10 mice and delayed the degeneration of retinal photoreceptors. It also improved the light responses of photoreceptors, bipolar cells and retinal ganglion cells. The expression of genes that are involved in inflammation, apoptosis and oxidative stress were up‐regulated in rd10 mice, and were reduced by ZD. ZD further reduced the activation of two key factors, signal transducer and activator of transcription 3 and chemokine (C‐C motif) ligand 2, down‐regulated the expression of the inflammatory factor GFAP, and inhibited extracellular signal regulated protein kinases and P38, but not the JNK pathways. In conclusion, ZD delays the degeneration of the rd10 retina both morphologically and functionally. Its anti‐inflammatory function is mediated primarily through the signal transducer and activator of transcription 3, chemokine (C‐C motif) ligand 2 and MAPK pathways. Thus, ZD may serve as a potential clinical candidate to treat RP. Oxidative stress and inflammatory responses are involved in the pathogenesis of retinal degeneration. We explored the protective effect and mechanism of a wolfberry‐derived small molecule Zeaxanthin dipalmitate (ZD) on degenerated photoreceptors in rd10 mice. ZD inhibits CCL2 (chemokine (C‐C motif) ligand 2), STAT3‐GFAP (Signal Transducers and Activators of Transcription‐Glial Fibrillary Acidic Protein) and ERK (Extracellular‐Regulated Kinase), P38 but not JNK (c‐Jun‐N‐terminal kinase) pathways to reduce inflammation. It also reduces ox