C1q-deficiency is neuroprotective against hypoxic-ischemic brain injury in neonatal mice.
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.
Ten
Vadim S
VS
Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA. vt82@columbia.edu
Sosunov
Sergei A
SA
Mazer
Sean P
SP
Stark
Raymond I
RI
Caspersen
Casper
C
Sughrue
Michael E
ME
Botto
Marina
M
Connolly
E Sander
ES
Pinsky
David J
DJ
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
D018696:Neuroprotective Agents; D012333:RNA, Messenger; D015922:Complement C1q