title: C1q-deficiency is neuroprotective against hypoxic-ischemic brain injury in neonatal mice.
abstract: OBJECTIVE
  This study was undertaken to determine whether the initial component of the classical complement (C) activation pathway contributes to hypoxic-ischemic brain injury in neonatal mice.
  
  
  METHODS
  Hypoxia-ischemia (HI) was produced in C1q(-/-) and wild-type (WT) neonatal mice. At 24 hours after HI, neonatal mouse reflex performance and cerebral infarct volume were assessed. Long-term outcomes were measured by water-maze performance and degree of cerebral atrophy at 7 to 8 weeks after HI. Activation of circulating neutrophils, and C1q, C3, and neutrophil deposition in brains were examined.
  
  
  RESULTS
  C1q(-/-) mice were significantly protected against HI (mean+/-SE infarct volume in C1q(-/-) mice=17.3+/-5.5% versus 53.6+/-6.8% in WT mice; P<0.0001) and exhibited significantly less neurofunctional deficit compared with WT mice. Immunostaining revealed significantly greater deposition of C3 (and C1q) as well as granulocytes in the infarcted brains in WT mice compared with C1q(-/-) animals. Activation of circulating leukocytes was significantly decreased in C1q(-/-) mice compared with WT mice, which correlated strongly (r=0.7) with cerebral infarct volumes.
  
  
  CONCLUSIONS
  Cerebral deposition of C1q and C3 after hypoxic-ischemic insult is associated with significantly greater neurologic damage in WT mice compared with C1q(-/-) mice, providing strong evidence that the classical C pathway contributes to the hypoxic-ischemic brain injury. Significantly decreased activation of circulating neutrophils associated with diminished local accumulation and attenuation of brain injury in C1q(-/-) mice suggests a potential cellular mechanism by which C1q mediates neurodegeneration in HI.
authors.affiliation: Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA. vt82@columbia.edu
authors.forename: Vadim S
authors.initials: VS
authors.lastname: Ten
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Sosunov
authors.forename: Sean P
authors.initials: SP
authors.lastname: Mazer
authors.forename: Raymond I
authors.initials: RI
authors.lastname: Stark
authors.forename: Casper
authors.initials: C
authors.lastname: Caspersen
authors.forename: Michael E
authors.initials: ME
authors.lastname: Sughrue
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology; D002560:Cerebrovascular Circulation; D003167:Complement Activation; D015922:Complement C1q / Q000172:deficiency* / Q000502:physiology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology*; D007150:Immunohistochemistry; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009504:Neutrophils / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012018:Reflex; D012039:Regional Blood Flow; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D018696:Neuroprotective Agents; D012333:RNA, Messenger; D015922:Complement C1q