{"doi":"10.1186/s40478-024-01906-9","title":"BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences","abstract":"Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.","journal":"Acta Neuropathologica Communications","year":2024,"id":433427,"datarank":0.40620753016533157,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.0,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9411,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1239145,"name":"Arya R. Vagadia","orcid":null,"position":1,"is_corresponding":false},{"id":1035238,"name":"Anh C. D. Le","orcid":null,"position":2,"is_corresponding":false},{"id":294087,"name":"Janet E. Baulch","orcid":"0000-0002-1078-6946","position":3,"is_corresponding":false},{"id":918610,"name":"Ding Quan Ng","orcid":"0000-0002-0754-7901","position":4,"is_corresponding":false},{"id":1239146,"name":"Mingyu Du","orcid":null,"position":5,"is_corresponding":false},{"id":52433,"name":"Kevin G. Johnston","orcid":"0000-0002-9381-9212","position":6,"is_corresponding":false},{"id":777168,"name":"Zhiqun Tan","orcid":"0000-0002-2235-4577","position":7,"is_corresponding":false},{"id":694019,"name":"Xiangmin Xu","orcid":"0000-0003-2775-8228","position":8,"is_corresponding":false},{"id":407805,"name":"Alexandre Chan","orcid":"0000-0003-4391-4219","position":9,"is_corresponding":false},{"id":232790,"name":"Munjal M. Acharya","orcid":"0000-0002-7767-5642","position":10,"is_corresponding":false},{"id":1034670,"name":"Sanad M. El-Khatib","orcid":"0000-0002-1697-2264","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:59:44.444627Z","pmid":"39696694","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":[]}