{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:41:57Z","timestamp":1785436917264,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK112803"],"award-info":[{"award-number":["DK112803"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK135995"],"award-info":[{"award-number":["DK135995"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"award":["DK112803"],"award-info":[{"award-number":["DK112803"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DK135995"],"award-info":[{"award-number":["DK135995"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute liver failure is often accompanied by neurological disturbances collectively referred to as hepatic encephalopathy (HE), characterized by neuroinflammation and subsequent cognitive decline. Insulin-like growth factor 1 (IGF1) is a neuroprotective peptide with anti-inflammatory properties in the brain. The role of IGF1 in cognitive deficits and neuroinflammation during HE remains largely unexplored. In C57Bl\/6 mice, HE was established through an intraperitoneal injection of azoxymethane (AOM), and tissues were collected at defined time points during disease development. IGF1 expression in the cortex was downregulated following AOM administration. Central infusion of recombinant mouse IGF1 (rmIGF1) before AOM injection resulted in delayed neurological impairment, reduced microglial activation, and decreased proinflammatory cytokine and chemokine production in AOM mice. In vitro, rmIGF1 and conditioned media derived from rmIGF1-treated primary neurons attenuated phagocytic activity and C\u2013C motif chemokine ligand 2 (CCL2) production in the microglial cell line EOC-20. Collectively, our results show that IGF1, whose levels decline during HE, alleviates neuroinflammation and improves the pathological state of AOM-treated mice through the suppression of microglial activation and the regulation of neuron\u2013microglia paracrine communication.<\/jats:p>","DOI":"10.3390\/ijms27083547","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T09:04:42Z","timestamp":1776330282000},"page":"3547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Central Administration of Recombinant IGF1 Is Neuroprotective in a Rodent Model of Acute Liver Failure"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7809-7471","authenticated-orcid":false,"given":"Yubo","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5980-0921","authenticated-orcid":false,"given":"Matthew","family":"McMillin","sequence":"additional","affiliation":[{"name":"Department of Innovation, Education and Technology, Baylor College of Medicine, Temple, TX 76508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Frampton","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaina","family":"Williams","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliet","family":"Venter","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jace","family":"Tyson","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esha","family":"Gupta","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihika","family":"Patankar","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8059-4041","authenticated-orcid":false,"given":"Patrick","family":"Mireles","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0511-9778","authenticated-orcid":false,"given":"Sharon","family":"DeMorrow","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA"},{"name":"Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e15619","DOI":"10.1111\/liv.15619","article-title":"Novel treatment of acute and acute-on-chronic liver failure: Interleukin-22","volume":"45","author":"Hwang","year":"2025","journal-title":"Liver Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.cld.2020.01.004","article-title":"Prognosis of Hepatic Encephalopathy","volume":"24","author":"Krishnarao","year":"2020","journal-title":"Clin. Liver Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1053\/j.gastro.2020.11.036","article-title":"Enhanced Meningeal Lymphatic Drainage Ameliorates Neuroinflammation and Hepatic Encephalopathy in Cirrhotic Rats","volume":"160","author":"Hsu","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.3748\/wjg.v16.i27.3347","article-title":"Changing face of hepatic encephalopathy: Role of inflammation and oxidative stress","volume":"16","author":"Seyan","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"106663","DOI":"10.1016\/j.nbd.2024.106663","article-title":"Brain incoming call from glia during neuroinflammation: Roles of extracellular vesicles","volume":"201","author":"Castelli","year":"2024","journal-title":"Neurobiol. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s40035-020-00221-2","article-title":"Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes","volume":"9","author":"Kwon","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"352","DOI":"10.14218\/JCTH.2019.00025","article-title":"The Direct Contribution of Astrocytes and Microglia to the Pathogenesis of Hepatic Encephalopathy","volume":"7","author":"Jaeger","year":"2019","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6855563","DOI":"10.1155\/jimr\/6855563","article-title":"The Role of Neuroinflammation in the Pathogenesis of Hepatic Encephalopathy","volume":"2025","author":"Rhodes","year":"2025","journal-title":"J. Immunol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"123413","DOI":"10.1016\/j.lfs.2025.123413","article-title":"Cell-cell communications in the brain of hepatic encephalopathy: The neurovascular unit","volume":"363","author":"Choi","year":"2025","journal-title":"Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12974-019-1455-y","article-title":"Elevated circulating TGF\u03b21 during acute liver failure activates TGF\u03b2R2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice","volume":"16","author":"McMillin","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1016\/S1734-1140(13)71523-8","article-title":"Possible contribution of IGF-1 to depressive disorder","volume":"65","author":"Slusarczyk","year":"2013","journal-title":"Pharmacol. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"147881","DOI":"10.1016\/j.brainres.2022.147881","article-title":"Anti-inflammatory and neuroprotective effects of insulin-like growth factor-1 overexpression in pentylenetetrazole (PTZ)-induced mouse model of chronic epilepsy","volume":"1785","author":"Wu","year":"2022","journal-title":"Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.pneurobio.2003.08.002","article-title":"Insulin-like growth factor-1 and post-ischemic brain injury","volume":"70","author":"Guan","year":"2003","journal-title":"Prog. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Labandeira-Garcia, J.L., Costa-Besada, M.A., Labandeira, C.M., Villar-Cheda, B., and Rodr\u00edguez-Perez, A.I. (2017). Insulin-Like Growth Factor-1 and Neuroinflammation. Front. Aging Neurosci., 9.","DOI":"10.3389\/fnagi.2017.00365"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"222","DOI":"10.4103\/1673-5374.226386","article-title":"Microglial dynamics during brain development","volume":"13","author":"Okajima","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"139753","DOI":"10.1016\/j.chemosphere.2023.139753","article-title":"Single-chemical and mixture effects of multiple volatile organic compounds exposure on liver injury and risk of non-alcoholic fatty liver disease in a representative general adult population","volume":"339","author":"Liu","year":"2023","journal-title":"Chemosphere"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/1742-2094-11-121","article-title":"Neuronal CCL2 is upregulated during hepatic encephalopathy and contributes to microglia activation and neurological decline","volume":"11","author":"McMillin","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s12974-016-0674-8","article-title":"Fractalkine suppression during hepatic encephalopathy promotes neuroinflammation in mice","volume":"13","author":"McMillin","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.neuroscience.2016.03.056","article-title":"The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity","volume":"325","author":"Dyer","year":"2016","journal-title":"Neuroscience"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.neuropharm.2016.02.034","article-title":"Early IGF-1 primes visual cortex maturation and accelerates developmental switch between NKCC1 and KCC2 chloride transporters in enriched animals","volume":"113","author":"Baroncelli","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1017\/cjn.2019.285","article-title":"Cortical Ribbon Sign in Acute Hepatic Encephalopathy with Sequential Atrophy","volume":"46","author":"Muir","year":"2019","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4456","DOI":"10.1038\/s41467-023-40081-8","article-title":"Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice","volume":"14","author":"Bai","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3531","DOI":"10.1016\/j.neuron.2023.08.005","article-title":"Active cortical networks promote shunting fast synaptic inhibition in vivo","volume":"111","author":"Burman","year":"2023","journal-title":"Neuron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3549","DOI":"10.1073\/pnas.1214912110","article-title":"Cortical energy demands of signaling and nonsignaling components in brain are conserved across mammalian species and activity levels","volume":"110","author":"Hyder","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.14309\/01.ajg.0000581996.67550.e4","article-title":"P: 5 Let7f Expression Is Upregulated in the Frontal Cortex During Acute Liver Failure and Contributes to Hepatic Encephalopathy via Downregulation of IGF1 Expression","volume":"114","author":"Williams","year":"2019","journal-title":"Off. J. Am. Coll. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.earlhumdev.2016.09.008","article-title":"IGF-1 in retinopathy of prematurity, a CNS neurovascular disease","volume":"102","author":"Liegl","year":"2016","journal-title":"Early Hum. Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e00829","DOI":"10.14309\/ctg.0000000000000829","article-title":"Serum Insulin-Like Growth Factor 1 and the Prognosis of Patients with Advanced Liver Diseases: A Meta-Analysis","volume":"16","author":"Liu","year":"2025","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_28","first-page":"469","article-title":"Chronic inflammation and the growth hormone\/insulin-like growth factor-1 axis","volume":"45","year":"2020","journal-title":"Cent. Eur. J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s10020-025-01074-z","article-title":"Endocrine and metabolic alterations in response to systemic inflammation and sepsis: A review article","volume":"31","author":"Mehdi","year":"2025","journal-title":"Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1515\/CCLM.2002.112","article-title":"Mechanisms of hyperammonemia","volume":"40","author":"Bachmann","year":"2002","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Adamu, A., Li, S., Gao, F., and Xue, G. (2024). The role of neuroinflammation in neurodegenerative diseases: Current understanding and future therapeutic targets. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1347987"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0301-0082(98)00083-5","article-title":"The role of microglia and macrophages in the pathophysiology of the CNS","volume":"58","author":"Stoll","year":"1999","journal-title":"Prog. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/nn1472","article-title":"ATP mediates rapid microglial response to local brain injury in vivo","volume":"8","author":"Davalos","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Pawelec, P., Ziemka-Nalecz, M., Sypecka, J., and Zalewska, T. (2020). The Impact of the CX3CL1\/CX3CR1 Axis in Neurological Disorders. Cells, 9.","DOI":"10.3390\/cells9102277"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s11011-007-9071-4","article-title":"Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension","volume":"22","author":"Wright","year":"2007","journal-title":"Metab. Brain Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.neuint.2009.11.010","article-title":"IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure","volume":"56","author":"Qu","year":"2010","journal-title":"Neurochem. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"20518","DOI":"10.1073\/pnas.1014557107","article-title":"Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline","volume":"107","author":"Terrando","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12468","DOI":"10.1073\/pnas.1511003112","article-title":"Imaging robust microglial activation after lipopolysaccharide administration in humans with PET","volume":"112","author":"Sandiego","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/glia.20467","article-title":"Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration","volume":"55","author":"Qin","year":"2007","journal-title":"Glia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1002\/cne.25274","article-title":"Ultrastructural analysis of the morphological phenotypes of microglia associated with neuroinflammatory cues","volume":"530","author":"Dyne","year":"2022","journal-title":"J. Comp. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jneuroim.2005.01.015","article-title":"Autocrine activation of microglia by tumor necrosis factor-alpha","volume":"162","author":"Kuno","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.2353\/ajpath.2008.080528","article-title":"Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice","volume":"173","author":"Janelsins","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.1016\/j.celrep.2019.07.078","article-title":"Microglia-Triggered Plasticity of Intrinsic Excitability Modulates Psychomotor Behaviors in Acute Cerebellar Inflammation","volume":"28","author":"Yamamoto","year":"2019","journal-title":"Cell Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1210\/me.2015-1087","article-title":"Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling","volume":"29","author":"McMillin","year":"2015","journal-title":"Mol. Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.ajpath.2019.10.003","article-title":"Thrombospondin-1 Exacerbates Acute Liver Failure and Hepatic Encephalopathy Pathology in Mice by Activating Transforming Growth Factor \u03b21","volume":"190","author":"Jefferson","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nrgastro.2013.99","article-title":"The liver-brain axis in liver failure: Neuroinflammation and encephalopathy","volume":"10","author":"Butterworth","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1111\/liv.14911","article-title":"2021 ISHEN guidelines on animal models of hepatic encephalopathy","volume":"41","author":"DeMorrow","year":"2021","journal-title":"Liver Int."},{"key":"ref_48","first-page":"G455","article-title":"Azoxymethane-induced fulminant hepatic failure in C57BL\/6J mice: Characterization of a new animal model","volume":"277","author":"Matkowskyj","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/S0140-6736(12)61728-0","article-title":"Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Lozano","year":"2012","journal-title":"Lancet"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3547\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T04:19:51Z","timestamp":1776485991000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3547"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":50,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27083547"],"URL":"https:\/\/doi.org\/10.3390\/ijms27083547","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]}}}