Lycium barbarum glycopeptide protects against inherited retinal degeneration in rd10 mice by regulating phototransduction and neuroinflammatory pathways.
Aug 2026· Neural Regeneration Research· Vol 21, pp. 5672-5680· 0 citations
Medicine
TL;DR
It is demonstrated that Lycium barbarum glycopeptide protects against inherited photoreceptor degeneration by improving retinal function and structure, alleviating neuroinflammation, and supporting phototransduction recovery.
Abstract
ABSTRACT
Inherited retinal degenerative diseases, such as retinitis pigmentosa, cause progressive photoreceptor loss and irreversible vision decline, yet effective treatments remain unavailable. Our previous studies demonstrated that Lycium barbarum glycopeptide delays photoreceptor degeneration in a chemically induced retinitis pigmentosa model, primarily through antiinflammatory mechanisms. In this study, we extended these findings to an inherited retinitis pigmentosa model to further elucidate the neuroprotective actions of Lycium barbarum glycopeptide. Lycium barbarum glycopeptide was orally administered daily to rd10 mice beginning at postnatal day 8, prior to photoreceptor degeneration, and retinal function and morphology were evaluated at postnatal day 25, the peak of rod apoptosis. Behavioral assays, electroretinography, immunofluorescence staining, proteomic profiling, and western blotting were performed to assess the therapeutic effects and molecular mechanisms of Lycium barbarum glycopeptide. Lycium barbarum glycopeptide treatment significantly improved visual performance in rd10 mice, as shown by enhanced optomotor responses and black.white transition behavior. Electroretinography analysis revealed increased scotopic a-wave amplitudes, indicating improved photoreceptor function. Histological evaluation showed preservation of outer nuclear layer thickness and maintenance of rod and cone opsin expression. Lycium barbarum glycopeptide also reduced microglial and Muller glial activation in a region-dependent manner. Proteomic and biochemical analyses revealed that Lycium barbarum glycopeptide upregulated key phototransduction proteins while concurrently downregulating pro-inflammatory mediators such as interleukin-6, nuclear factor kappa B, cyclooxygenase-2, and tumor necrosis factor-α. Collectively, these results demonstrate that Lycium barbarum glycopeptide protects against inherited photoreceptor degeneration by improving retinal function and structure, alleviating neuroinflammation, and supporting phototransduction recovery. This work extends our previous findings and highlights Lycium barbarum glycopeptide as a promising therapeutic candidate for inherited retinal degenerative diseases.
Retinal degeneration is characterized by progressive photoreceptor loss driven by oxidative stress and chronic inflammation, yet effective mutation-independent therapeutic strategies remain limited. Lycium barbarum polysaccharides (LBPs) possess antioxidant and anti-inflammatory activities; however, the structural features responsible for their retinal protective effects remain poorly defined. In this study, crude LBP was fractionated by DEAE-cellulose ion-exchange chromatography, and the most bioactive fraction, LBPF2, was identified using H2O2-injured 661W cone photoreceptor-like cells. LBPF2 was subsequently characterized by high-performance anion-exchange chromatography, SEC-MALLS-RI, GC–MS methylation analysis, and one- and two-dimensional NMR spectroscopy, and its protective effects were evaluated in H2O2-treated 661W cells and rd10 mice. LBPF2 was identified as a homogeneous glucose-rich polysaccharide with an average molecular weight of approximately 41 kDa and a backbone mainly composed of →4)-α-D-Glcp-(1→ and →4,6)-α-D-Glcp-(1→ residues. LBPF2 reduced oxidative stress, inflammation, and apoptosis in H2O2-treated 661W cells, preserved retinal morphology, improved electroretinographic responses and partial retention of rhodopsin immunoreactivity relative to untreated rd10 mice, and restored redox homeostasis in rd10 mice. Pharmacological inhibition of Nrf2 using ML385 attenuated these protective effects, supporting the involvement of Nrf2/HO-1 signaling. Collectively, these findings identify LBPF2 as a structurally characterized neuroprotective polysaccharide that mitigates retinal degeneration through coordinated regulation of oxidative stress and inflammation and highlight its therapeutic potential for retinal degenerative diseases.
Yijing Yang, Shu-Ting Yin, Ying Deng et al.· Antioxidants· 0 citations
Retinal degeneration (RD) is a group of retinopathies characterized by progressive photoreceptor death and chronic neuroinflammation. Quercetin (QUE) is a natural flavonol with potent anti-inflammatory and free-radical scavenging properties. However, its protective effects against RD remain poorly characterized. This study aims to investigate the therapeutic potential of QUE on RD.In vitro and in vivo models of sodium iodate (NaIO3)-induced oxidative damage were used to evaluate the effects of QUE in RD. NaIO3 was used to induce oxidative damage in 661W cells. QUE was added to the cell cultures, and cell viability and oxidative markers were assessed. In vivo, QUE was delivered into the vitreous cavity of NaIO3-induced RD mice, followed by morphological analysis, visual function evaluation, behavioral testing, and Western blot detection.QUE protected 661W cells from NaIO3-induced oxidative damage by reducing intracellular reactive oxygen species, restoring mitochondrial membrane potential, and alleviating mitochondrial membrane pore disruption. In vivo, intravitreal QUE injection preserved retinal structure, reduced lesion area, elevated electroretinogram P-wave amplitude, and improved behavioral performance. QUE administration was accompanied by alleviated oxidative stress, inhibited glial activation, reduced pro-inflammatory cytokines, and elevated p-PI3K and p-AKT expression in RD. Neuroinflammation and oxidative stress are involved in RD pathology. These findings provide preliminary evidence that QUE exerts protective effects on photoreceptors in NaIO₃-induced RD. No causal relationship between PI3K/AKT activation and the retinal protection of QUE was established in this study.
The hypothesis that there is a biochemical link, most likely the UPR, between rhodopsin folding/misfolding status and metabolic homeostasis is supported and targeted metabolic modulation may offer a complementary therapeutic avenue for treating RP.
M. Murthy, Hannah Staggs-Sandy, Paniz Jasbi et al.· The FASEB Journal· 0 citations
Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal degenerative disorders characterized by progressive photoreceptor loss and vision impairment, for which broadly applicable mutation-independent therapies remain limited. To examine the therapeutic potential of combined galanin receptor 3 (GALR3) inhibition and antioxidant therapy in a mutation-independent context, we utilized the rd10 mouse model of RP. We first evaluated the effects of individual treatments with the GALR3 antagonist SNAP-37889 and the antioxidant quercetin, followed by a combined treatment regimen to determine whether simultaneous targeting of neuroinflammatory and oxidative stress pathways provides enhanced retinal protection. Treatment efficacy was assessed using functional and morphological analyses, including electroretinography (ERG) to measure retinal function, optical coherence tomography (OCT) to evaluate retinal structure in vivo, and histological and immunohistochemical analyses to quantify photoreceptor survival and markers of retinal oxidative stress and inflammation. Although the expression levels of individual inflammatory and oxidative stress markers did not consistently exhibit additive responses, the combined treatment produced greater photoreceptor survival and preservation of photopic retinal function than either monotherapy alone. These findings support the hypothesis that simultaneous modulation of oxidative stress and neuroinflammation provides greater neuroprotective benefits, establish a foundation for the development of mutation-independent therapeutic strategies for RP, and identify GALR3 as a promising therapeutic target.
Maria Azam, Ming-Da Liu, Beata Jastrzebska· Antioxidants· 0 citations
A novel mechanistic link is revealed among WDR34, retrograde IFT, ciliopathies, and retinal degeneration, providing potential therapeutic insights for ciliopathy-associated RP and its contribution to retinal degeneration.
Bo Jia, Jianan Xie, Xuebin Zhou et al.· Investigative Ophthalmology...· 0 citations
PRPH2 mutations cause inherited retinal dystrophies (IRDs), but how photoreceptor outer segment (OS) disruption reshapes the surrounding retina remains unclear. Using a heterozygous Prph2C213Y/+ mouse model generated by CRISPR/Cas9, we characterized age-related retinal pathology and responses of retinal pigment epithelium (RPE) and Müller glia. Independent age- and sex-matched cohorts were examined at 1, 3, and 6 months by electroretinography, optical coherence tomography, and fundus autofluorescence. Mutant mice showed rod dysfunction from 1 month, RPE dysfunction from 3 months, and cone dysfunction by 6 months, accompanied by progressive outer retinal thinning and hyperautofluorescent deposits. Histological and ultrastructural analyses revealed OS disorganization, shortened RPE microvilli, RPE monolayer remodeling, increased RPE autofluorescence, and reactive Müller gliosis. Single-cell spatial transcriptomics of wild-type and mutant retinas at 6 months resolved nine cell populations and identified RPE cells and Müller glia as prominently perturbed non-photoreceptor populations. RPE cells showed an epithelial-mesenchymal transition-related remodeling state linked to a candidate Nfib-Fstl1 module, whereas Müller glia showed activation of activator protein 1 (AP-1) regulons, including Fos, Fosl2, and Junb, with predicted targets Osmr, A2m, and Stat3. Cell-cell communication analyses indicated coordinated changes in neuroprotective, inflammatory, and matrix-related signaling from RPE cells and Müller glia toward photoreceptors. These findings indicate that PRPH2-associated retinal dystrophy is a multicellular process in which OS disruption drives coordinated RPE and Müller glial remodeling with potentially protective or pro-degenerative effects, and nominate the RPE Nfib-Fstl1 program, Müller glial AP-1 responses with predicted STAT3 involvement, and support-cell-derived growth factor signaling as candidate mutation-independent therapeutic targets.
Haoxin Guo, Linfei Wei, Binghan Chen et al.· Neurobiology of Disease· 0 citations
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