title: Glatiramer Acetate administration does not reduce damage after cerebral ischemia in mice.
abstract: Inflammation plays a key role in ischemic stroke pathophysiology: microglial/macrophage cells and type-1 helper cells (Th1) seem deleterious, while type-2 helper cells (Th2) and regulatory T cells (Treg) seem protective. CD4 Th0 differentiation is modulated by microglial cytokine secretion. Glatiramer Acetate (GA) is an immunomodulatory drug that has been approved for the treatment of human multiple sclerosis by means of a number of mechanisms: reduced microglial activation and pro-inflammatory cytokine production, Th0 differentiation shifting from Th2 to Th2 and Treg with anti-inflammatory cytokine production and increased neurogenesis. We induced permanent (pMCAo) or transient middle cerebral artery occlusion (tMCAo) and GA (2 mg) or vehicle was injected subcutaneously immediately after cerebral ischemia. Mice were sacrificed at D3 to measure neurological deficit, infarct volume, microglial cell density and qPCR of TNFα and IL-1β (pro-inflammatory microglial cytokines), IFNγ (Th2 cytokine), IL-4 (Th2 cytokine), TGFβ and IL-10 (Treg cytokines), and at D7 to evaluate neurological deficit, infarct volume and neurogenesis assessment. We showed that in GA-treated pMCAo mice, infarct volume, microglial cell density and cytokine secretion were not significantly modified at D3, while neurogenesis was enhanced at D7 without significant infarct volume reduction. In GA-treated tMCAo mice, microglial pro-inflammatory cytokines IL-1β and TNFα were significantly decreased without modification of microglial/macrophage cell density, cytokine secretion, neurological deficit or infarct volume at D3, or modification of neurological deficit, neurogenesis or infarct volume at D7. In conclusion, Glatiramer Acetate administered after cerebral ischemia does not reduce infarct volume or improve neurological deficit in mice despite a significant increase in neurogenesis in pMCAo and a microglial pro-inflammatory cytokine reduction in tMCAo.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Angiogenesis and Translational Research Center, INSERM U965, F-75475 Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Poittevin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Deroide
authors.forename: Feriel
authors.initials: F
authors.lastname: Azibani
authors.forename: Claude
authors.initials: C
authors.lastname: Delcayre
authors.forename: Claire
authors.initials: C
authors.lastname: Giannesini
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Levy
authors.forename: Marc
authors.initials: M
authors.lastname: Pocard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kubis
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy* / Q000209:etiology* / Q000401:mortality; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000068717:Glatiramer Acetate; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000188:drug therapy / Q000401:mortality; D007279:Injections, Subcutaneous; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009460:Neurologic Examination; D009479:Neuropeptides / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage*; D012333:RNA, Messenger; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000145:classification / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D000089622:Doublecortin Domain Proteins; D007166:Immunosuppressive Agents; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D010455:Peptides; D012333:RNA, Messenger; D000068717:Glatiramer Acetate; D001973:Bromodeoxyuridine