Pharmacological complement inhibition at the C3 convertase level promotes neuronal survival, neuroprotective intracerebral gene expression, and neurological outcome after traumatic brain injury.
The complement system represents an important mediator of neuroinflammation in traumatic brain injury. We have previously shown that transgenic mice with central nervous system-targeted overexpression of Crry, a potent murine complement inhibitor at the level of C3 convertases, are protected from complement-mediated neuropathological sequelae in brain-injured mice. This knowledge was expanded in the present study to a pharmacological approach by the use of a recombinant Crry molecule (termed Crry-Ig) which was recently made available in a chimeric form fused to the non-complement fixing mouse IgG1 Fc region. In a standardized model of closed head injury in mice, the systemic injection of 1 mg Crry-Ig at 1 h and 24 h after trauma resulted in a significant neurological improvement for up to 7 days, as compared to vehicle-injected control mice (P < 0.05, repeated measures ANOVA). Furthermore, the extensive neuronal destruction seen in the hippocampal CA3/CA4 sublayers in head-injured mice with vehicle injection only was shown to be preserved - to a similar extent as in "sham"-operated mice - by the posttraumatic injection of Crry-Ig. Real-time RT-PCR analysis revealed that the post-treatment with Crry-Ig resulted in a significant up-regulation of candidate neuroprotective genes in the injured hemisphere (Bcl-2, C1-Inh, CD55, CD59), as compared to the vehicle control group (P < 0.01, unpaired Student's t test). Increased intracerebral Bcl-2 expression by Crry-Ig treatment was furthermore confirmed at the protein level by Western blot analysis. These data suggest that pharmacological complement inhibition represents a promising approach for attenuation of neuroinflammation and secondary neurodegeneration after head injury.
Leinhase
Iris
I
Department of Trauma and Reconstructive Surgery, Charité-University Medical School, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Schmidt
Oliver I
OI
Thurman
Joshua M
JM
Hossini
Amir M
AM
Rozanski
Michal
M
Taha
Mohy E
ME
Scheffler
Alice
A
John
Thilo
T
Smith
Wade R
WR
Holers
V Michael
VM
Stahel
Philip F
PF
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011951:Receptors, Complement / Q000008:administration & dosage*; D017463:Receptors, Complement 3b; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D015599:Trauma Severity Indices
C081470:Cr1l protein, mouse; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D003165:Complement System Proteins