title: Reparative effects of interleukin-1 receptor antagonist in young and aged/co-morbid rodents after cerebral ischemia.
abstract: Neuroprotective strategies for ischemic stroke have failed to translate from bench to bedside, possibly due to the lack of consideration of key clinical co-morbidities. Stroke and co-morbidities are associated with raised levels of the pro-inflammatory cytokine interleukin-1 (IL-1). Inhibition of IL-1 by the administration of interleukin-1 receptor antagonist (IL-1Ra) has shown to be neuroprotective after experimental cerebral ischemia. Stroke can also trigger a robust neuroreparative response following injury, yet many of these new born neurons fail to survive or integrate into pre-existing circuits. Thus, we explore here effects of IL-1Ra on post-stroke neurogenesis in young and aged/co-morbid rats. Aged lean, aged Corpulent (a model of atherosclerosis, obesity and insulin resistance) and young Wistar male rats were exposed to transient cerebral ischemia, received subcutaneous IL-1Ra 3 and 6h during reperfusion, and effects on stroke outcome and neurogenesis were analyzed. Our results show that administration of IL-1Ra improves stroke outcome in both young and aged/co-morbid rats. Furthermore, IL-1Ra not only increases stem cell proliferation, but also significantly enhances neuroblast migration and the number of newly born neurons after cerebral ischemia. Overall, our data demonstrate that systemic administration of IL-1Ra improves outcome and promotes neurogenesis after experimental stroke, further highlighting the therapeutic potential of this clinically approved drug.
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense (UCM) and Instituto de Investigación 12 de Octubre (i+12), Madrid, Spain. Electronic address: jmpradil@ucm.es.
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Pradillo
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Department of Neurology, Yale School of Medicine, New Haven, USA.
authors.forename: Katie N
authors.initials: KN
authors.lastname: Murray
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: Graham A
authors.initials: GA
authors.lastname: Coutts
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense (UCM) and Instituto de Investigación 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Moraga
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense (UCM) and Instituto de Investigación 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Oroz-Gonjar
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: Herve
authors.initials: H
authors.lastname: Boutin
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense (UCM) and Instituto de Investigación 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Moro
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense (UCM) and Instituto de Investigación 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Lizasoain
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Rothwell
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. Electronic address: stuart.allan@manchester.ac.uk.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allan
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy*; D002465:Cell Movement / Q000187:drug effects; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy*; D013997:Time Factors
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D018696:Neuroprotective Agents
keywords: Cerebral ischemia; Co-morbidity; Interleukin-1 receptor antagonist; Neurogenesis; Neuroprotection; Risk factors