{"doi":"10.1042/cs20250943","title":"The ICU environment paradigm as a strategy to enhance the validity of delirium animal models","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>Delirium is common in ICU patients and associated with adverse outcomes. We hypothesized that an ICU-like environment would enhance model validity by amplifying behavioral and neurobiological alterations. Male Wistar rats (50 days old) underwent sterile laparotomy or cecal ligation and puncture (CLP)-induced sepsis, with or without exposure to an ICU-like environment. Behavioral tests (open field, Y-maze, SHIRPA) were performed at 0–36 h, along with assessments of reactive oxygen species, glial markers, neurotransmitters, and delirium incidence/severity. Predictive validity was evaluated in the most severe condition (CLP + ICU) using minocycline, dexmedetomidine, and rivastigmine. The ICU-like environment exacerbated behavioral deficits consistent with human delirium and increased their severity. We observed elevations in IL-6 (hippocampus, cortex, and plasma in laparotomy; hippocampus in sepsis) and IL-1β (cortex in laparotomy), alongside aminergic/excitatory imbalance (dopamine, noradrenaline, and glutamate). In sepsis + ICU, minocycline and dexmedetomidine reduced IL-1β/IL-6 and improved behavioral performance; rivastigmine improved selected behavioral domains, increased acetylcholine, and reduced AChE activity; dexmedetomidine decreased ROS; and minocycline and rivastigmine attenuated microgliosis. The ICU-like environment worsened behavioral and neurochemical changes, surgery plus anesthesia, and sepsis, supporting its value for enhancing model validity.</jats:p>","journal":"Clinical Science","year":2026,"id":608343,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1562346,"name":"Carla Sasso Simon","orcid":null,"position":1,"is_corresponding":false},{"id":1562348,"name":"Daniel Paulo Bortoluzzi","orcid":null,"position":2,"is_corresponding":false},{"id":1562350,"name":"Carlos Henrique Silva Galant","orcid":null,"position":3,"is_corresponding":false},{"id":1562352,"name":"Andriele Gonçalves Marcon","orcid":null,"position":4,"is_corresponding":false},{"id":1562354,"name":"Yasmin Isé Marcelino","orcid":null,"position":5,"is_corresponding":false},{"id":1562356,"name":"Diana Vieira da Silva","orcid":null,"position":6,"is_corresponding":false},{"id":1562358,"name":"Mary Hellen Aléssio Nervis","orcid":null,"position":7,"is_corresponding":false},{"id":1562360,"name":"Mariane Amanda de Oliveira","orcid":null,"position":8,"is_corresponding":false},{"id":1562362,"name":"Julia Rossi Cândido","orcid":null,"position":9,"is_corresponding":false},{"id":1562364,"name":"Edson de Oliveira Zaldguer","orcid":null,"position":10,"is_corresponding":false},{"id":1562365,"name":"Nicoly Silveira Apolidório","orcid":null,"position":11,"is_corresponding":false},{"id":1562367,"name":"Karine Borges de Medeiros","orcid":null,"position":12,"is_corresponding":false},{"id":371495,"name":"Thomas Fenzl","orcid":"0000-0002-0132-9591","position":13,"is_corresponding":false},{"id":1143842,"name":"Nadia Lunardi","orcid":"0000-0002-4433-2934","position":14,"is_corresponding":false},{"id":660141,"name":"Tatiana Barichello","orcid":"0000-0001-7776-8454","position":15,"is_corresponding":false},{"id":1562369,"name":"Carlos Henrique R. 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Male Wistar rats (50 days old) underwent sterile laparotomy or cecal ligation and puncture (CLP)-induced sepsis, with or without exposure to an ICU-like environment. Behavioral tests (open field, Y-maze, SHIRPA) were performed at 0–36 h, along with assessments of reactive oxygen species, glial markers, neurotransmitters, and delirium incidence/severity. Predictive validity was evaluated in the most severe condition (CLP + ICU) using minocycline, dexmedetomidine, and rivastigmine. The ICU-like environment exacerbated behavioral deficits consistent with human delirium and increased their severity. We observed elevations in IL-6 (hippocampus, cortex, and plasma in laparotomy; hippocampus in sepsis) and IL-1β (cortex in laparotomy), alongside aminergic/excitatory imbalance (dopamine, noradrenaline, and glutamate). In sepsis + ICU, minocycline and dexmedetomidine reduced IL-1β/IL-6 and improved behavioral performance; rivastigmine improved selected behavioral domains, increased acetylcholine, and reduced AChE activity; dexmedetomidine decreased ROS; and minocycline and rivastigmine attenuated microgliosis. The ICU-like environment worsened behavioral and neurochemical changes, surgery plus anesthesia, and sepsis, supporting its value for enhancing model validity.</jats:p>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41873684","pmcid":null,"openalex_id":"https://openalex.org/W7140199112","authors":[],"funders":[{"funder_name":"Texas Alzheimer's Research and Care Consortium","grant_id":"TARCC,2022-26","title":null},{"funder_name":"HHS | National Institutes of Health","grant_id":"1R01 AG072491","title":null},{"funder_name":"Conselho Nacional de Desenvolvimento Científico e Tecnológico","grant_id":"408662/2024-7","title":null},{"funder_name":"National Football League Players Association","grant_id":"","title":null},{"funder_name":"National Football League Players Association (NFLPA)","grant_id":"","title":null},{"funder_name":"National Football League Players Association (NFLPA)","grant_id":"","title":null}],"total_grants":6,"fwci":9.6975,"citation_percentile":0.9653951,"influential_citations":0,"citation_trend":[{"year":2026,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://portlandpress.com/clinsci/article-pdf/140/4/537/986274/cs-2025-0943.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1042/cs20250943","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41873684","host_type":"repository"}],"fields_of_study":["Intensive Care Unit Cognitive Disorders","Sepsis Diagnosis and Treatment","Anesthesia and Sedative Agents","Animals","Delirium","Male","Disease Models, Animal","Rats, Wistar","Behavior, Animal","Sepsis","Intensive Care Units","Reactive Oxygen Species","Dexmedetomidine","Rats"],"mesh_terms":["Rivastigmine","Animals","Behavior, Animal","Delirium","Disease Models, Animal","Intensive Care Units","Male","Minocycline","Rats, Wistar","Reactive Oxygen Species","Sepsis","Dexmedetomidine","Rats"],"keywords":["Delirium","Dexmedetomidine","Neurochemical","Adverse effect","Organic mental disorders","Minocycline","Neuroinflammation","Hippocampus","Neurotransmitters","Animal model","Icu-like Environment"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Life in Land"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-30T12:03:37.273647Z","pmid":null,"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":[]}