C1q-Deficiency Is Neuroprotective Against Hypoxic-Ischemic Brain Injury in Neonatal Mice

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Abstract
Background and Purpose— 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 −/− 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.