{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:58:39Z","timestamp":1792789119778,"version":"4.5.0"},"reference-count":34,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Kentucky Neuroscience Research Priority Area","id":[{"id":"https:\/\/ror.org\/02k3smh20","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NeuSTAR Neurosurgery Award"},{"name":"CNS-Met COBRE","award":["P20 GM148326\/GM\/NIGMS NIH HHS\/United States"],"award-info":[{"award-number":["P20 GM148326\/GM\/NIGMS NIH HHS\/United States"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Oxidative stress due to increased reactive oxygen species (ROS) formation and\/or inflammation is considered to play an important role in ischemic stroke injury. Leukemia inhibitory factor (LIF) has been shown to protect both oligodendrocytes and neurons from ischemia by upregulating endogenous anti-oxidants, though the effect of ischemia and the protective role of LIF treatment in mitochondrial function have not been studied. The goal of this study was to determine whether LIF protects ischemia-induced altered mitochondrial bioenergetics in reproductively senescent aged rats of both sexes (\u226518 months old), approximately equivalent to the average age of human stroke patients. Animals were euthanized at 3 days after permanent middle cerebral artery occlusion (MCAO) surgery. We found that MCAO surgery significantly reduced mitochondrial oxidative phosphorylation in both the ipsilateral striatum and prefrontal cortex in male aged rats compared to their respective contralateral regions of the brain. MCAO injury showed mitochondrial bioenergetic dysfunction only in the striatum in female rats; however, the prefrontal cortex remained unaffected to the injury. LIF-treated rats significantly prevented mitochondrial dysfunction in the striatum in male rats compared to their vehicle-treated counterparts. Collectively, MCAO-induced mitochondrial dysfunction and LIF\u2019s potential as a therapeutic biomolecule exhibited sex- and tissue-specific effects, varying between the striatum and prefrontal cortex in male and female rats.<\/jats:p>","DOI":"10.3390\/biom15050738","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T06:54:28Z","timestamp":1747724068000},"page":"738","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sex- and Tissue-Specific Effects of Leukemia Inhibitory Factor on Mitochondrial Bioenergetics Following Ischemic Stroke"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5945-5235","authenticated-orcid":false,"given":"Hemendra J.","family":"Vekaria","sequence":"first","affiliation":[{"name":"Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 405036, USA"},{"name":"Lexington Veterans Affairs Healthcare System, Lexington, KY 40502, USA"},{"name":"Department of Neurosurgery, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7271-0111","authenticated-orcid":false,"given":"Sarah J.","family":"Shelley","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Kentucky, Lexington, KY 40506, USA"},{"name":"The Center for Advanced Translational Stroke Science, University of Kentucky (CATSS), Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Sarah J.","family":"Messmer","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Kentucky, Lexington, KY 40506, USA"},{"name":"The Center for Advanced Translational Stroke Science, University of Kentucky (CATSS), Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Prashant D.","family":"Kunjadia","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Kentucky, Lexington, KY 40506, USA"},{"name":"The Center for Advanced Translational Stroke Science, University of Kentucky (CATSS), Lexington, KY 40506, USA"},{"name":"Department of Neuroscience, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5434-9748","authenticated-orcid":false,"given":"Christopher J.","family":"McLouth","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Biostatistics, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7418-4760","authenticated-orcid":false,"given":"Patrick G.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 405036, USA"},{"name":"Lexington Veterans Affairs Healthcare System, Lexington, KY 40502, USA"},{"name":"Department of Neuroscience, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Justin F.","family":"Fraser","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Kentucky, Lexington, KY 40506, USA"},{"name":"The Center for Advanced Translational Stroke Science, University of Kentucky (CATSS), Lexington, KY 40506, USA"},{"name":"Department of Neuroscience, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Neurology, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Radiology, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Otolaryngology, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Keith R.","family":"Pennypacker","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Kentucky, Lexington, KY 40506, USA"},{"name":"The Center for Advanced Translational Stroke Science, University of Kentucky (CATSS), Lexington, KY 40506, USA"},{"name":"Department of Neuroscience, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Neurology, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1959-9100","authenticated-orcid":false,"given":"Chirayu D.","family":"Pandya","sequence":"additional","affiliation":[{"name":"Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 405036, USA"},{"name":"Department of Neurosurgery, University of Kentucky, Lexington, KY 40506, USA"},{"name":"The Center for Advanced Translational Stroke Science, University of Kentucky (CATSS), Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1706442","article-title":"Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct","volume":"378","author":"Nogueira","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3531","DOI":"10.1177\/0271678X17705259","article-title":"Intra-arterial verapamil post-thrombectomy is feasible, safe, and neuroprotective in stroke","volume":"37","author":"Fraser","year":"2017","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E4","DOI":"10.3171\/2017.1.FOCUS16514","article-title":"Neuroprotective delivery platforms as an adjunct to mechanical thrombectomy","volume":"42","author":"Babadjouni","year":"2017","journal-title":"Neurosurg. Focus"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.jocn.2019.08.001","article-title":"Neuroprotection for ischemic stroke in the endovascular era: A brief report on the future of intra-arterial therapy","volume":"69","author":"Griauzde","year":"2019","journal-title":"J. Clin. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1177\/1591019920925677","article-title":"Intra-arterial neuroprotective therapy as an adjunct to endovascular intervention in acute ischemic stroke: A review of the literature and future directions","volume":"26","author":"Link","year":"2020","journal-title":"Interv. Neuroradiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1093\/brain\/118.4.1027","article-title":"On the mechanisms underlying hypoxia-induced membrane depolarization in striatal neurons","volume":"118","author":"Calabresi","year":"1995","journal-title":"Brain"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Jurcau, A., and Ardelean, A.I. (2022). Oxidative Stress in Ischemia\/Reperfusion Injuries following Acute Ischemic Stroke. Biomedicines, 10.","DOI":"10.3390\/biomedicines10030574"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Salaudeen, M.A., Bello, N., Danraka, R.N., and Ammani, M.L. (2024). Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones. Biomolecules, 14.","DOI":"10.3390\/biom14030305"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/nrm3479","article-title":"Mitochondria: Master regulators of danger signalling","volume":"13","author":"Galluzzi","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1177\/1352458514544537","article-title":"The central role of mitochondria in axonal degeneration in multiple sclerosis","volume":"20","author":"Campbell","year":"2014","journal-title":"Mult. Scler."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Matuz-Mares, D., Gonzalez-Andrade, M., Araiza-Villanueva, M.G., Vilchis-Landeros, M.M., and Vazquez-Meza, H. (2022). Mitochondrial Calcium: Effects of Its Imbalance in Disease. Antioxidants, 11.","DOI":"10.3390\/antiox11050801"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.brainres.2011.01.102","article-title":"Focal cerebral ischemia and mitochondrial dysfunction in the TNFalpha-transgenic rat","volume":"1384","author":"Pandya","year":"2011","journal-title":"Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.mito.2017.12.005","article-title":"Metabolic defects in multiple sclerosis","volume":"44","author":"Adiele","year":"2019","journal-title":"Mitochondrion"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/S0165-5728(00)00241-1","article-title":"Saturable entry of leukemia inhibitory factor from blood to the central nervous system","volume":"106","author":"Pan","year":"2000","journal-title":"J. Neuroimmunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/nm0602-613","article-title":"LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival","volume":"8","author":"Butzkueven","year":"2002","journal-title":"Nat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1097\/01.jnen.0000235855.77716.25","article-title":"Leukemia inhibitory factor arrests oligodendrocyte death and demyelination in spinal cord injury","volume":"65","author":"Azari","year":"2006","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1186\/s12974-018-1326-y","article-title":"Leukemia inhibitory factor modulates the peripheral immune response in a rat model of emergent large vessel occlusion","volume":"15","author":"Davis","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1172\/JCI200114660","article-title":"gp130 cytokine signaling in the pituitary gland: A paradigm for cytokine-neuro-endocrine pathways","volume":"108","author":"Arzt","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/S0006-8993(01)03156-0","article-title":"Leukemia inhibitory factor by systemic administration rescues spinal motor neurons in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis","volume":"922","author":"Azari","year":"2001","journal-title":"Brain Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1111\/ejn.12675","article-title":"Leukemia inhibitor factor promotes functional recovery and oligodendrocyte survival in rat models of focal ischemia","volume":"40","author":"Rowe","year":"2014","journal-title":"Eur. J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1007\/s12035-015-9587-2","article-title":"Leukemia Inhibitory Factor Protects Neurons from Ischemic Damage via Upregulation of Superoxide Dismutase 3","volume":"54","author":"Davis","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2174\/156720206776875849","article-title":"Sigma receptor activation reduces infarct size at 24 hours after permanent middle cerebral artery occlusion in rats","volume":"3","author":"Ajmo","year":"2006","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1089\/neu.2020.7379","article-title":"Time-Course Evaluation of Brain Regional Mitochondrial Bioenergetics in a Pre-Clinical Model of Severe Penetrating Traumatic Brain Injury","volume":"38","author":"Pandya","year":"2021","journal-title":"J. Neurotrauma"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"114574","DOI":"10.1016\/j.expneurol.2023.114574","article-title":"Azithromycin reduces hemoglobin-induced innate neuroimmune activation","volume":"372","author":"Pandya","year":"2024","journal-title":"Exp. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.trsl.2021.01.005","article-title":"Hemoglobin induces oxidative stress and mitochondrial dysfunction in oligodendrocyte progenitor cells","volume":"231","author":"Pandya","year":"2021","journal-title":"Transl. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Vekaria, H.J., Kalimon, O.J., Prajapati, P., Velmurugan, G.V., and Sullivan, P.G. (2024). An efficient and high-throughput method for the evaluation of mitochondrial dysfunction in frozen brain samples after traumatic brain injury. Front. Mol. Biosci., 11.","DOI":"10.3389\/fmolb.2024.1378536"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12974-019-1516-2","article-title":"Neuroinflammation: Friend and foe for ischemic stroke","volume":"16","author":"Jayaraj","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kalimon, O.J., Vekaria, H.J., Prajapati, P., Short, S.L., Hubbard, W.B., and Sullivan, P.G. (2024). The Uncoupling Effect of 17\u03b2-Estradiol Underlies the Resilience of Female-Derived Mitochondria to Damage after Experimental TBI. Life, 14.","DOI":"10.3390\/life14080961"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.brainres.2018.11.017","article-title":"Efficacy of leukemia inhibitory factor as a therapeutic for permanent large vessel stroke differs among aged male and female rats","volume":"1707","author":"Davis","year":"2019","journal-title":"Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8880244","DOI":"10.1155\/2020\/8880244","article-title":"The Poststroke Peripheral Immune Response Is Differentially Regulated by Leukemia Inhibitory Factor in Aged Male and Female Rodents","volume":"2020","author":"Davis","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.4049\/jimmunol.177.4.2088","article-title":"TLR7 ligands induce higher IFN-alpha production in females","volume":"177","author":"Frommer","year":"2006","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Cao, W. (2022). IFN-Aging: Coupling Aging With Interferon Response. Front. Aging, 3.","DOI":"10.3389\/fragi.2022.870489"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"108485","DOI":"10.1016\/j.celrep.2020.108485","article-title":"Heterogeneous Escape from X Chromosome Inactivation Results in Sex Differences in Type I IFN Responses at the Single Human pDC Level","volume":"33","author":"Hagen","year":"2020","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1002\/eji.201646725","article-title":"Human pDCs display sex-specific differences in type I interferon subtypes and interferon \u03b1\/\u03b2 receptor expression","volume":"47","author":"Ziegler","year":"2017","journal-title":"Eur. J. Immunol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/5\/738\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:46:53Z","timestamp":1790671613000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/5\/738"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,20]]},"references-count":34,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["biom15050738"],"URL":"https:\/\/doi.org\/10.3390\/biom15050738","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,20]]}}}