{"doi":"10.1371/journal.pone.0320231","title":"Long-term functional rescue of trauma-induced vision loss by a novel, small molecule TrkB modulator","abstract":"Brain-derived neurotrophic factor (BDNF) signaling through the tropomyosin-related kinase B (TrkB) receptor promotes neuronal growth and survival following an injury. However, its short half-life and pleiotropic effects limit the clinical use of BDNF as a therapy in neurodegenerative disorders. Identification of novel and selective TrkB activators may ameliorate the damage caused to retinal neurons during eye-related injuries and may reduce adverse visual outcomes associated with visual trauma. We previously described a small molecule, N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC), that activates TrkB and reduces the decline in visual function in a mouse model of ocular trauma. Using the lead optimization approach, we subsequently synthesized a fluoropyridine analog of HIOC, 2-fluoro-N-(2-(5-hydroxy-1H-indol-3-yl) ethyl) nicotinamide (HIFN), which also successfully activates TrkB. HIFN is a more potent TrkB modulator than the parent compound, HIOC. Further, treatment with HIFN demonstrated neuroprotection in an animal model of overpressure ocular blast injury, ameliorating blast-related visual functional decline. Mice treated with HIFN had better visual acuity, contrast sensitivity, and retinal function supported by enhanced survival of retinal ganglion cells compared to vehicle-treated animals. Moreover, HIFN exhibited better protective effects than HIOC. The therapeutic effects of HIFN were attributed to TrkB activation, as blocking the receptor with a selective receptor antagonist (ANA-12) abrogated the neuroprotection. Together, our results identify HIFN, a novel TrkB receptor modulator, as a strategy for decreasing retinal degeneration and progressive vision loss associated with traumatic ocular injury. In addition, this compound may have broader applications in treating other diseases with altered TrkB activity.","journal":"PLoS ONE","year":2025,"id":576264,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"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":258663,"name":"Christopher J. Walker","orcid":"0000-0002-1819-7388","position":1,"is_corresponding":false},{"id":318122,"name":"Micah A. Chrenek","orcid":"0000-0002-1366-5963","position":2,"is_corresponding":false},{"id":420140,"name":"Hans E. Grossniklaus","orcid":"0000-0003-0178-9712","position":3,"is_corresponding":false},{"id":1186902,"name":"Frank E. McDonald","orcid":"0000-0002-6612-7106","position":4,"is_corresponding":false},{"id":318126,"name":"P. Michael Iuvone","orcid":"0000-0002-2510-3896","position":5,"is_corresponding":false},{"id":1215126,"name":"Shweta Modgil","orcid":null,"position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:57:56.636458Z","pmid":"41021607","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":[]}