title: Site-targeted complement inhibition by a complement receptor 2-conjugated inhibitor (mTT30) ameliorates post-injury neuropathology in mouse brains.
abstract: Intracerebral complement activation after severe traumatic brain injury (TBI) leads to a cascade of neuroinflammatory pathological sequelae that propagate host-mediated secondary brain injury and adverse outcomes. There are currently no specific pharmacological agents on the market to prevent or mitigate the development of secondary cerebral insults after TBI. A novel chimeric CR2-fH compound (mTT30) provides targeted inhibition of the alternative complement pathway at the site of tissue injury. This experimental study was designed to test the neuroprotective effects of mTT30 in a mouse model of closed head injury. The administration of 500 μg mTT30 i.v. at 1 h, 4 h and 24 h after head injury attenuated complement C3 deposition in injured brains, reduced the extent of neuronal cell death, and decreased post-injury microglial activation, compared to vehicle-injected placebo controls. These data imply that site-targeted alternative pathway complement inhibition may represent a new promising therapeutic avenue for the future management of severe TBI.
authors.affiliation: Department of Orthopaedic Surgery, Denver Health Medical Center and University of Colorado School of Medicine, Denver, CO 80204, USA.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Rich
authors.affiliation: Department of Orthopaedic Surgery, Denver Health Medical Center and University of Colorado School of Medicine, Denver, CO 80204, USA.
authors.forename: Chesleigh N
authors.initials: CN
authors.lastname: Keene
authors.affiliation: Department of Orthopaedic Surgery, Denver Health Medical Center and University of Colorado School of Medicine, Denver, CO 80204, USA.
authors.forename: Miriam D
authors.initials: MD
authors.lastname: Neher
authors.affiliation: Alexion Pharmaceuticals, Cheshire, CT 06410, USA.
authors.forename: Krista
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Alexion Pharmaceuticals, Cheshire, CT 06410, USA.
authors.forename: Zhao-Xue
authors.initials: ZX
authors.lastname: Yu
authors.affiliation: Department of Orthopaedic Surgery, Denver Health Medical Center and University of Colorado School of Medicine, Denver, CO 80204, USA.
authors.forename: Antoine
authors.initials: A
authors.lastname: Ganivet
authors.affiliation: Department of Medicine and Department of Immunology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.affiliation: Department of Orthopaedic Surgery, Denver Health Medical Center and University of Colorado School of Medicine, Denver, CO 80204, USA; Department of Neurosurgery, University of Colorado School of Medicine, Denver, CO 80204, USA. Electronic address: philip.stahel@dhha.org.
authors.forename: Philip F
authors.initials: PF
authors.lastname: Stahel
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D003176:Complement C3 / Q000378:metabolism; D051056:Complement Inactivating Agents / Q000627:therapeutic use*; D016489:Head Injuries, Closed / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*
chemical_list: C000597269:CR2-fH protein; D003176:Complement C3; D051056:Complement Inactivating Agents; D018696:Neuroprotective Agents; D011993:Recombinant Fusion Proteins
keywords: CR2-conjugated pharmacological compounds; Neuroinflammation; Secondary brain injury; Site-targeted complement inhibition; Traumatic brain injury