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Table 2 Summary of studies investigating the role of complement in TBI using animal models

From: Correction to: 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.