{"doi":"10.3389/fnsys.2020.546531","title":"The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats","abstract":"Background: Children exposed to general anesthesia early in life may develop significant neurodevelopmental abnormalities. Establishing safer pediatric anesthesia is impeded by a lack of understanding of the initial mediating mechanisms of such effects. Here, we tested the roles of the sex steroid 17β-estradiol (E2) and excitatory GABA type A receptor signaling, whose specific developmental effects in rodents occur during the age period of increased vulnerability to the developmental effects of general anesthetics. Methods: Sprague-Dawley rats were pretreated with the inhibitors of E2 synthesis, formestane, or the Na+-K+-2Cl- (NKCC1) Cl- importer, bumetanide, prior to anesthesia with 2.1% sevoflurane for 6 h on postnatal (P) day 4, P5, or P6. The subsequent exposure to sevoflurane-induced electroencephalography-detectable seizures (P~10), behavior during the elevated plus maze (EPM, P~60) and prepulse inhibition of acoustic startle (PPI, P~70) tests, and corticosterone responses to stress (P~80) were studied. Results: Sevoflurane induced increased susceptibility to repeated exposure to sevoflurane-caused electroencephalography-detectable seizures (F(3,24) = 7.445, P = 0.001) and behavioral deficiencies in male rats during the EPM (F(3,55) = 4.397, P = 0.008) and PPI (F(3,110) = 5.222, P = 0.003) tests. The corticosterone responses to stress were increased in males (F(3,16) = 11.906, P < 0.001) and females (F(3,20) = 11.010, P < 0.001). Formestane and bumetanide prevented these effects of sevoflurane. Conclusion: These results, along with previously published data, suggest that sevoflurane-enhanced E2 synthesis and excitatory GABAAR signaling, which may be further positively modulated by E2, represent initial steps in the developmental effects of the anesthetic.","journal":"Frontiers in Systems Neuroscience","year":2020,"id":82970,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":427739,"name":"Baofeng Yang","orcid":"0000-0002-0125-1608","position":1,"is_corresponding":false},{"id":427740,"name":"Ling-Sha Ju","orcid":"0000-0001-7266-0794","position":2,"is_corresponding":false},{"id":328370,"name":"Jiaojiao Yang","orcid":"0000-0002-8611-4089","position":3,"is_corresponding":false},{"id":429083,"name":"Andrea Allen","orcid":null,"position":4,"is_corresponding":false},{"id":427741,"name":"Jiaqiang Zhang","orcid":"0000-0002-1367-9644","position":5,"is_corresponding":false},{"id":427742,"name":"Anatoly E. Martynyuk","orcid":"0000-0002-9915-5584","position":6,"is_corresponding":false},{"id":427738,"name":"Jie Wang","orcid":"0000-0002-2997-3450","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-18T21:54:09.383533Z","pmid":"33013333","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":[]}