Table 2 Summary of studies investigating the role of complement in TBI using animal models
From: The role of the complement system in traumatic brain injury: a review
Study | Species | Model | Treatment | Complement pathway(s) | Relevant finding(s) |
|---|---|---|---|---|---|
Kaczorowski et al., 1995 [79] | Rat | Standardized weight-drop | • WT + sCR1 • WT + vehicle | All | Rats treated with sCR1 had reduced brain neutrophil infiltration compared to vehicle-treated rats, suggesting that complement plays a role in the neuroinflammatory response induced by TBI. |
Yang et al., 2006 [80] | Mouse | Intracerebral hemorrhage (ICH) | • C3-/- • WT | All | C3-/- mice, when compared with WT mice, showed reduced brain oedema, lower hemeoxygenase-1 levels, and reduced microglia activation and neutrophil infiltration after injury. The C3-/- mice also displayed reduced forelimb dysfunction in comparison with WT mice. |
Sewell et al., 2004 [81] | Mouse | Cryoinjury | • C3-/- • C5-/- • WT + C5aR antagonist • WT | All | Injury size and neutrophil infiltration were significantly reduced in C3-/- mice compared with WT mice. Neutrophil infiltration was also found to be reduced in C5-/- mice and WT mice treated with a C5aR antagonist compared with untreated WT mice. |
Rancan et al., 2003 [83] | Mouse | Standardized weight-drop model (focal closed head injury) | • GFAP-sCrry • WT | All | GFAP-sCrry mice were found to have reduced neurological deficits and BBB compromise compared with WT mice exposed to the same TBI-like injury. |
Leinhase et al., 2006a [84] | Mouse | Standardized weight-drop | • WT + Crry-Ig • WT + vehicle | All | Administration of Crry-Ig 1 and 24 hrs after injury was associated with a reduction in tissue loss and improvement in neurological function when compared with vehicle-treated mice. |
Garrett et al., 2009 [85] | Mouse | ICH | • WT + C5aR antagonist • WT + C5aR antagonist + C3aR antagonist • WT + vehicle | All | Administration of a C5aR antagonist alone, or both C5aR and C3aR antagonists, to WT mice was associated with a reduced deficit in neurological function and reduced spatial memory dysfunction compared with vehicle-treated WT mice. These effects were also associated with a reduction in leukocyte infiltration and oedema A synergistic effect was observed upon administration of both antagonists. |
Stahel et al., 2009 [88] | Mouse | Standardized weight-drop | • CD59a-/- • WT | All | CD95a-/- mice had significantly worse neurological outcomes than WT mice 7 days post-injury. Neuronal cell death in CD59a-/- mice was also greater than that in WT mice, as indicated both by serum NSE levels as well as TUNEL histochemistry. |
Fluiter et al., 2014 [89] | Mouse | Standardized weight-drop | • WT + OmCI • WT + C6 antisense • WT + vehicle | All | Interfering with MAC formation, by administering OmCI or C6 antisense to WT mice, was associated with a reduction in neuronal death, microglial activation and neurological deficit, compared with vehicle-treated WT mice. |
Ruseva et al., 2015 [90] | Mouse | Standardized weight-drop | • WT + CD59-2a-CRIg • WT + vehicle | All | CD59-2a-CRIg was found to inhibit MAC formation in vitro. In vivo administration of CD59-2a-CRIg reduced MAC formation, neuronal damage, and microglial activation compared to vehicle treated controls. Neurological outcomes were ameliorated with CD59-2a-CRIg administration. |
Leinhase et al., 2006b [91] | Mouse | Standardized weight-drop | • fB-/- • WT | Alternative | fB-/- mice were found to have reduced neuronal loss, upregulation of the anti-apoptotic regulatory protein Bcl-2, and downregulation of the pro-apoptotic Fas receptor, compared with WT mice subsequent to a TBI-like injury. |
Leinhase et al., 2007 [92] | Mouse | Standardized weight-drop | • WT + mab1379 • WT | Alternative | Administration of mab1379, a monoclonal antibody directed against fB, 1 or 24 hrs after injury was associated with reduced neuronal loss, an attenuated inflammatory response, as well as upregulation of genes associated with neuroprotection, in comparison with vehicle administration. |
You et al., 2007 [82] | Mouse | Controlled cortical impact (CCI) | • C3-/- • C4-/- • C4-/- + hC4 • WT | • All (C3) • Classical and lectin (C4) | C3-/- mice were found to have reduced brain leukocyte infiltration compared to WT, but there were no differences between them in terms of injury size or neurological deficits. C4-/- mice showed decreased brain tissue damage and reduced motor deficits, compared to WT, after CCI. These improvements were reversed if recombinant human C4 (hC4) was administered to C4-/- mice. |
Longhi et al., 2009 [93] | Mouse | CCI | • WT + C1-INH • WT | Classical and lectin | Mice given C1-INH 10 mins after injury developed smaller contusions, and had reduced cognitive and motor dysfunction compared to vehicle-treated controls. Delayed administration of C1-INH (60 mins post-injury) led to a reduction in motor dysfunction, but had no effect on cognitive deficits or contusion size. |
Longhi et al., 2014 [75] | Mouse | CCI | • MBL-/- • WT | Lectin | MBL-C and MBL-A immunostaining was upregulated 30 mins post-injury, and this lasted for a week. MBL-A immunostaining was less prominent. Neuronal loss in MBL-A/MBL-C knockout (MBL-/-) mice was reduced when compared with wildtypes 5 weeks post-injury, which was paralleled by a reduction in sensorimotor impairment when assessed 2-4 weeks post-lesion. |
Yager et al., 2008 [94] | Mouse | CCI | • MBL-/- • WT | Lectin | 6 hrs post-injury, increased neurodegeneration was observed in the hippocampi of MBL-/- mice when compared with WT mice. Neurological deficits in MBL-/- mice were also greater than those in WT mice, when assessed a week after injury. |