{"doi":"10.1101/2025.05.06.652467","title":"Idebenone Enhances the Early Microglial Response to Traumatic Brain Injury and Mitigates Acute Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways","abstract":"ABSTRACT Traumatic Brain Injury (TBI) leads to persistent pro-inflammatory microglial activation implicated in neurodegeneration. Idebenone, a coenzyme Q10 analogue that interacts with both mitochondria and the tyrosine kinase adaptor SHC1, inhibits aspects of microglial activation in vitro . We used the NanoString Neuropathology panel to test the hypothesis that idebenone post-treatment mitigates TBI pathology-associated acute gene expression changes by moderating the pro-inflammatory microglial response to injury. Controlled cortical impact to adult male mice increased the microglial activation signature in peri-lesional cortex at 24 hours post-TBI. Unexpectedly, several microglial signature genes upregulated by TBI were further increased by post-injury idebenone administration. However, idebenone significantly attenuated TBI-mediated perturbations to gene expression associated with behavior, particularly in the gene ontology:biological process (GO:BP) pathways “ephrin receptor signaling” and “dopamine metabolic process.” Gene co-expression analysis correlated levels of microglial complement component 1q ( C1q ) and the neurotrophin receptor gene Ntrk1 to large (>3-fold) TBI-induced decreases in dopamine receptor genes Drd1 and Drd2 that were mitigated by idebenone treatment. Bioinformatics analysis identified SUZ12 as a candidate transcriptional regulator of idebenone-modified gene expression changes. Overall, results suggest that idebenone enhances TBI-induced microglial proliferation within the first 24 hours of TBI and identify Ephrin-A and dopamine signaling as novel idebenone targets.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":565711,"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":0.959,"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":1229563,"name":"Chinmoy Sarkar","orcid":"0000-0001-5508-8968","position":1,"is_corresponding":false},{"id":1449753,"name":"Boris Piskoun","orcid":null,"position":2,"is_corresponding":false},{"id":1449330,"name":"Naibo Zhang","orcid":"0000-0003-2138-4798","position":3,"is_corresponding":false},{"id":1449331,"name":"Apurva Borcar","orcid":"0000-0001-6706-1025","position":4,"is_corresponding":false},{"id":278147,"name":"Courtney Robertson","orcid":"0000-0002-2561-3837","position":5,"is_corresponding":false},{"id":655205,"name":"Marta M. Lipinski","orcid":"0000-0002-7537-9014","position":6,"is_corresponding":false},{"id":250456,"name":"Nagendra Yadava","orcid":"0000-0002-6202-2673","position":7,"is_corresponding":false},{"id":1449332,"name":"Molly J. Goodfellow","orcid":"0009-0006-1582-352X","position":8,"is_corresponding":false},{"id":488069,"name":"Brian M. Polster","orcid":"0000-0003-2571-7510","position":9,"is_corresponding":false},{"id":1449752,"name":"Hyehyun Hwang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T02:56:32.546082Z","pmid":"40654680","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":[]}