{"doi":"10.1186/s12974-024-03329-8","title":"Ibuprofen reduces inflammation, necroptosis and protects photoreceptors from light-induced retinal degeneration","abstract":"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 lx of light for 2-4 hours (h). 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). Cell death genes were analyzed at 24 and 72 h after LD using the Mouse Pan-Cell Death Pathway PCR Array (88 genes). The cellular location and protein expression of key necroptosis genes were assessed by immunohistochemistry. RESULTS: Retinal outer nuclear layer (ONL) thickness in vehicle-injected LD animals was 8.7 ± 0.6% of retinas without LD (p < 0.0001). In IBU 200 mg/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 hour 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 no LD levels in LD IBU-treated mice. Microglia activation and MLKL protein upregulation were observed primarily in photoreceptors 12 h 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.","journal":"Journal of Neuroinflammation","year":2025,"id":514156,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9645,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1376748,"name":"Zi-He Wan","orcid":null,"position":1,"is_corresponding":false},{"id":1363578,"name":"Weifeng Li","orcid":"0000-0002-0244-2908","position":2,"is_corresponding":false},{"id":628962,"name":"Kavita Vats","orcid":"0000-0002-1491-348X","position":3,"is_corresponding":false},{"id":1376153,"name":"Kunal Mehta","orcid":"0000-0001-7402-1291","position":4,"is_corresponding":false},{"id":1376749,"name":"Laura Fan","orcid":null,"position":5,"is_corresponding":false},{"id":232271,"name":"Lingli Zhou","orcid":"0000-0002-9321-9348","position":6,"is_corresponding":false},{"id":639932,"name":"Xi Li","orcid":"0000-0001-6325-3230","position":7,"is_corresponding":false},{"id":1376750,"name":"Gloria Li","orcid":null,"position":8,"is_corresponding":false},{"id":562814,"name":"Casey Keuthan","orcid":"0000-0001-9422-490X","position":9,"is_corresponding":false},{"id":280703,"name":"Cynthia Berlinicke","orcid":"0000-0003-1014-0800","position":10,"is_corresponding":false},{"id":1177222,"name":"Cheng Qian","orcid":"0000-0003-3182-7396","position":11,"is_corresponding":false},{"id":717864,"name":"Noriko Esumi","orcid":"0000-0001-7995-4023","position":12,"is_corresponding":false},{"id":232276,"name":"Elia J. Duh","orcid":"0000-0003-1917-373X","position":13,"is_corresponding":false},{"id":6902,"name":"Donald J. Zack","orcid":"0000-0002-7966-1973","position":14,"is_corresponding":false},{"id":1376747,"name":"Ping‐Wu Zhang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:48:23.284782Z","pmid":"39875939","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}