Effective protection of photoreceptors using an inflammation-responsive hydrogel to attenuate outer retinal degeneration

Kim, Hyerim; Roh, Hyeonhee; Kim, Sang-Heon; Lee, Kangwon; Im, Maesoon; Oh, Seung Ja

doi:10.1038/s41536-023-00342-y

Cited by 2 publications

References 52 publications

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Ibuprofen reduces inflammation, necroptosis and protects photoreceptors from light-induced retinal degeneration

Zhang,

Wan,

et al. 2024

Preprint

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Background The retinal degenerative diseases retinitis pigmentosa (RP) and atrophic age- related macular degeneration (AMD) are characterized by vision loss from photoreceptor (PR) degeneration. Unfortunately, current treatments for these diseases are limited at best. Genetic and other preclinical evidence suggest a relationship between retinal degeneration and inflammation. To further explore this relationship, we tested whether Ibuprofen (IBU), an FDA-approved non-steroidal anti-inflammatory drug (NSAID), could promote PR survival and function in a mouse model of light damage (LD)-induced PR degeneration. Methods LD was induced by exposing mice to 4000 lux of light for 2–4 hrs. IBU (100 or 200 mg/kg) or vehicle was administered by daily intraperitoneal injection. Retinal structure and function were evaluated by spectral-domain optical coherence tomography (SD-OCT) and electroretinography (ERG). The cell death genes were analyzed at 24 and 72 hours (hrs) after LD by the Mouse Pan-Cell Death Pathway PCR Array (88 genes). The cellular location and protein expression of the key necroptosis gene was assessed by immunohistochemistry. Results Retinal outer nuclear layer (ONL) thickness in the vehicle-injected animals was 8.7 ± 0.6% of retinas without LD (p < 0.0001). In IBU 200mg/kg treated mice, central ONL thickness was 74.9 ± 7.7% of untreated retinas (p < 0.001). A-wave and b-wave ERG amplitudes were significantly preserved in IBU-treated animals. IBU significantly inhibited retinal inflammation. Twenty-four hrs after LD, retinal mRNA expression for the inflammatory-factors tumor necrosis factor (Tnf), interleukin-1 beta (Il1b), and C-C motif chemokine ligand 2 (Ccl2) increased by 10, 17 and 533-fold, respectively; in IBU-treated animals, the expression levels of these inflammatory factors were not significantly different from no-LD controls. Expression of key necroptosis genes, including Ripk3 and Mlkl, were upregulated in LD vehicle-treated mice, but dramatically reduced to near the no LD levels in LD IBU-treated mice. Microglia activation and MLKL protein upregulation were observed primarily in photoreceptors 12 hrs after LD, as assessed by immunohistochemistry. IBU reduced the upregulation of MLKL protein and microglia migration in the ONL and outer plexiform layer (OPL) of treated retinas. Conclusions Systemic administration of the anti-inflammatory drug IBU partially protected mouse retinas from light-induced photochemical damage and inhibited both inflammation and the necroptosis cell death pathways. Our results suggest that NSAIDs may provide a promising therapeutic approach for treatment of the human retinal degenerative diseases.

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Ibuprofen reduces inflammation, necroptosis and protects photoreceptors from light-induced retinal degeneration

Zhang,

Wan,

et al. 2024

Preprint

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Development of TRIB3-Based Therapy as a Gene-Independent Approach to Treat Retinal Degenerative Disorders

Ung,

Starr,

Zhylkibayev

et al. 2024

IJMS

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Inherited retinal degeneration (RD) constitutes a heterogeneous group of genetic retinal degenerative disorders. The molecular mechanisms underlying RD encompass a diverse spectrum of cellular signaling, with the unfolded protein response (UPR) identified as a common signaling pathway chronically activated in degenerating retinas. TRIB3 has been recognized as a key mediator of the PERK UPR arm, influencing various metabolic pathways, such as insulin signaling, lipid metabolism, and glucose homeostasis, by acting as an AKT pseudokinase that prevents the activation of the AKT → mTOR axis. This study aimed to develop a gene-independent approach targeting the UPR TRIB3 mediator previously tested by our group using a genetic approach in mice with RD. The goal was to validate a therapeutic approach targeting TRIB3 interactomes through the pharmacological targeting of EGFR-TRIB3 and delivering cell-penetrating peptides targeting TRIB3 → AKT. The study employed rd10 and P23H RHO mice, with afatinib treatment conducted in p15 rd10 mice through daily intraperitoneal injections. P15 P23H RHO mice received intraocular injections of cell-penetrating peptides twice at a 2-week interval. Our study revealed that both strategies successfully targeted TRIB3 interactomes, leading to an improvement in scotopic A- and B-wave ERG recordings. Additionally, the afatinib-treated mice manifested enhanced photopic ERG amplitudes accompanied by a delay in photoreceptor cell loss. The treated rd10 retinas also showed increased PDE6β and RHO staining, along with an elevation in total PDE activity in the retinas. Consequently, our study demonstrated the feasibility of a gene-independent strategy to target common signaling in degenerating retinas by employing a TRIB3-based therapeutic approach that delays retinal function and photoreceptor cell loss in two RD models.

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Effective protection of photoreceptors using an inflammation-responsive hydrogel to attenuate outer retinal degeneration

Cited by 2 publications

References 52 publications

Ibuprofen reduces inflammation, necroptosis and protects photoreceptors from light-induced retinal degeneration

Ibuprofen reduces inflammation, necroptosis and protects photoreceptors from light-induced retinal degeneration

Development of TRIB3-Based Therapy as a Gene-Independent Approach to Treat Retinal Degenerative Disorders

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