title: Receptor for complement peptide C3a: a therapeutic target for neonatal hypoxic-ischemic brain injury.
abstract: Complement is an essential component of inflammation that plays a role in ischemic brain injury. Recent reports demonstrate novel functions of complement in normal and diseased CNS, such as regulation of neurogenesis and synapse elimination. Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI), a model of neonatal HI encephalopathy. HI injury was induced at postnatal day 9 (P9), and loss of hippocampal tissue was determined on P31. We compared WT mice with transgenic mice expressing C3a under the control of glial fibrillary acidic protein promoter, which express biologically active C3a only in CNS and without the requirement of a priori complement activation. Further, we injected C3a peptide into the lateral cerebral ventricle of mice lacking the C3a receptor (C3aR) and WT mice and assessed HI-induced memory impairment 41 d later. We found that HI-induced tissue loss in C3a overexpressing mice was reduced by 50% compared with WT mice. C3a peptide injected 1 h after HI protected WT but not C3aR-deficient mice against HI-induced memory impairment. Thus, C3a acting through its canonical receptor ameliorates behavioral deficits after HI injury, and C3aR is a novel therapeutic target for the treatment of neonatal HI encephalopathy.
authors.affiliation: Perinatal Center, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Järlestedt
authors.forename: Catherine I
authors.initials: CI
authors.lastname: Rousset
authors.forename: Anders
authors.initials: A
authors.lastname: Ståhlberg
authors.forename: Hana
authors.initials: H
authors.lastname: Sourkova
authors.forename: Alison L
authors.initials: AL
authors.lastname: Atkins
authors.forename: Claire
authors.initials: C
authors.lastname: Thornton
authors.forename: Scott R
authors.initials: SR
authors.lastname: Barnum
authors.forename: Rick A
authors.initials: RA
authors.lastname: Wetsel
authors.forename: Mike
authors.initials: M
authors.lastname: Dragunow
authors.forename: Milos
authors.initials: M
authors.lastname: Pekny
authors.forename: Carina
authors.initials: C
authors.lastname: Mallard
authors.forename: Henrik
authors.initials: H
authors.lastname: Hagberg
authors.forename: Marcela
authors.initials: M
authors.lastname: Pekna
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015926:Complement C3a / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011951:Receptors, Complement / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a
keywords: behavioral deficit; mice