1. ¹Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
2. ²Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
3. ³Developmental Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
4. ⁴Vascular Medicine Research Unit, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
5. ⁵Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
6. ⁶CBR Institute for Biomedical Research, Inc., Harvard Medical School, Boston, Massachusetts, USA

Correspondence: Dr M Whalen, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. E-mail: mwhalen@partners.org

Received 18 December 2006; Revised 16 February 2007; Accepted 12 March 2007; Published online 25 April 2007.

Abstract

Complement component C4 mediates C3-dependent tissue damage after systemic ischemia–reperfusion injury. Activation of C3 also contributes to the pathogenesis of experimental and human traumatic brain injury (TBI); however, few data exist regarding the specific pathways (classic, alternative, and lectin) involved. Using complement knockout mice and a controlled cortical impact (CCI) model, we tested the hypothesis that the classic pathway mediates secondary damage after TBI. After CCI, C4c and C3d immunostaining were detected in cortical vascular endothelial cells in wild-type (WT) mice; however, C4c and C3d immunostaining were also detected in C1q^-/- mice, and C3d immunostaining was detected in C4^-/- mice. After CCI, WT and C1q^-/- mice had similar motor deficits, Morris water maze performance, and brain lesion size. Naive C4^-/- and WT mice did not differ in baseline motor performance, but C4^-/- mice had reduced postinjury motor deficits (days 1 to 7, P<0.05) and decreased brain tissue damage (days 14 and 35, P<0.05) versus WT. Reconstitution of C4^-/- mice with human C4 (hC4) reversed their protection against postinjury motor deficits (P<0.05 versus vehicle), but administration of hC4 did not impair postinjury motor performance (versus vehicle) in WT mice. The protective effects of C4^-/- were functionally distinct from the classic pathway and terminal complement, as C1q^-/- and C3^-/- mice had postinjury tissue damage and motor dysfunction similar to WT. Thus, C4 contributes to motor deficits and brain tissue damage after CCI by mechanism(s) fundamentally different from those involved in experimental systemic ischemia–reperfusion injury.