title: Sub-acute systemic erythropoietin administration reduces ischemic brain injury in an age-dependent manner.
abstract: Stroke is associated with neuroinflammation, neuronal loss and blood-brain barrier (BBB) breakdown. Thus far, recombinant tissue-type plasminogen activator (rtPA), the only approved treatment for acute ischemic stroke, increases the risk of intracerebral hemorrhage and is poorly efficient in disaggregating platelet-rich thrombi. Therefore, the development of safer and more efficient therapies is highly awaited. Encouraging neuroprotective effects were reported in mouse models of ischemic stroke following administration of erythropoietin (EPO). However, previous preclinical studies did not investigate the effects of EPO in focal ischemic stroke induced by a platelet-rich thrombus and did not consider the implication of age. Here, we performed middle cerebral artery occlusion by inducing platelet-rich thrombus formation in chimeric 5- (i.e. young) and 20- (i.e. aged) months old C57BL/6 mice, in which hematopoietic stem cells carried the green fluorescent protein (GFP)-tag. Recombinant human EPO (rhEPO) was administered 24 hours post-occlusion and blood-circulating monocyte populations were studied by flow cytometry 3 hours post-rhEPO administration. Twenty-four hours following rhEPO treatment, neuronal loss and BBB integrity were assessed by quantification of Fluoro-Jade B (FJB)-positive cells and extravasated serum immunoglobulins G (IgG), respectively. Neuroinflammation was determined by quantifying infiltration of GFP-positive bone marrow-derived cells (BMDC) and recruitment of microglial cells into brain parenchyma, along with monocyte chemotactic protein-1 (MCP-1) brain protein levels. Here, rhEPO anti-inflammatory properties rescued ischemic injury by reducing neuronal loss and BBB breakdown in young animals, but not in aged littermates. Such age-dependent effects of rhEPO must therefore be taken into consideration in future studies aiming to develop new therapies for ischemic stroke.
authors.affiliation: Neuroscience Laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Thériault
authors.affiliation: Neuroscience Laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Le Béhot
authors.affiliation: Neuroscience Laboratory, CHU de Québec Research Center and Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Québec City, QC, Canada.
authors.forename: Ayman
authors.initials: A
authors.lastname: ElAli
authors.affiliation: Neuroscience Laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
mesh_terms: D000367:Age Factors; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000009:adverse effects / Q000627:therapeutic use*; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020768:Middle Cerebral Artery / Q000473:pathology; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D020521:Stroke / Q000150:complications / Q000188:drug therapy*; D013927:Thrombosis / Q000139:chemically induced
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C554270:EPO protein, human; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D004921:Erythropoietin; D049452:Green Fluorescent Proteins
keywords: Gerotarget; aging; erythropoietin; inflammation; ischemic stroke; monocyte chemotactic protein-1