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      Reparative effects of interleukin-1 receptor antagonist in young and aged/co-morbid rodents after cerebral ischemia

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          Highlights

          • IL-1β is a key proinflammatory cytokine involved in ischemic brain damage.

          • Administration of IL-1Ra improves the stroke outcome in young and co-morbid rats.

          • Acute IL-1Ra administration also promotes neurogenesis after experimental stroke.

          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 6 h 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.

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          Most cited references36

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          Neuronal replacement from endogenous precursors in the adult brain after stroke.

          In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.
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            CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury.

            We have reviewed a battery of useful tests for evaluating sensorimotor function and plasticity acutely and chronically in unilateral rat models of central nervous system injury. These tests include forelimb use for weight shifting during vertical exploration in a cylindrical enclosure, an adhesive removal test of sensory function, and forelimb placing. These tests monitor recovery of sensorimotor function independent of the extent of test experience. Data are presented for four models, including permanent focal ischemia, focal injury to the forelimb area of sensorimotor cortex, dopaminergic neurodegeneration of the nigrostriatal system, and cervical spinal cord injury. The effect of the dendrite growth promoting factor, Osteogenic Protein-1 (OP-1) on outcome following permanent middle cerebral artery (MCA) occlusion was used as an example to illustrate how the tests can be applied preclinically. OP-1 showed a beneficial effect on limb use asymmetry in the cylinder test.
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              The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis.

              Adult animals continue to produce new neurons in the dentate gyrus of hippocampus. Until now, the principal method of studying neurogenesis has been to inject either tritiated thymidine or 5'-Bromo-2-deoxyuridine (BrdU) intraperitoneally followed by autoradiographic or immunohistochemical detection methods respectively. However, such exogenous markers may produce toxic effects. Our objective was to determine whether Ki-67, a nuclear protein expressed in all phases of the cell cycle except the resting phase, can be used as an alternative, endogenous marker. Using immunohistochemistry, we examined Ki-67 and BrdU expression pattern in rats. Ki-67 was expressed within the proliferative zone of the dentate gyrus and its expression pattern mimicked that of BrdU when examined soon after exogenous BrdU administration. Quantitative comparison of BrdU and Ki-67-positive cells showed 50% higher numbers of the latter when examined 24 h after the BrdU injection. This was expected, since BrdU can be incorporated into DNA only during the S-phase of the mitotic process, whereas Ki-67 is expressed for its whole duration. Experimental increases (by ischemia) or reductions (by radiation) in the number of mitotic cells produced parallel changes in BrdU and Ki-67 signals. Thus, Ki-67 is an effective mitotic marker and has most of the benefits of BrdU and none of the costs. This study provides evidence for Ki-67 to be used as a marker of proliferation in the initial phase of adult neurogenesis.
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                Author and article information

                Contributors
                Journal
                Brain Behav Immun
                Brain Behav. Immun
                Brain, Behavior, and Immunity
                Elsevier
                0889-1591
                1090-2139
                1 March 2017
                March 2017
                : 61
                : 117-126
                Affiliations
                [a ]Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
                [b ]Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense (UCM) and Instituto de Investigación 12 de Octubre (i+12), Madrid, Spain
                [c ]Department of Neurology, Yale School of Medicine, New Haven, USA
                Author notes
                [* ]Corresponding authors at: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040, Madrid (J.M. Pradillo). AV Hill Building, Oxford Road, Manchester, M13 9PT (S.M. Allan). jmpradil@ 123456ucm.es stuart.allan@ 123456manchester.ac.uk
                [1]

                Both authors have contributed equally to this work.

                Article
                S0889-1591(16)30515-3
                10.1016/j.bbi.2016.11.013
                5325120
                27856349
                04175778-4c68-4980-94ea-5df63ec7fed4
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 7 June 2016
                : 21 October 2016
                : 12 November 2016
                Categories
                Full-length Article

                Neurosciences
                cerebral ischemia,interleukin-1 receptor antagonist,neuroprotection,neurogenesis,co-morbidity,risk factors

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