Neuroprotective Effects Of Apolipoprotein E Mimetic Peptide-COG1410 After Traumatic Brain Injury

Objective: Blood brain barrier(BBB)disruption,inflammatory response and cerebral glucose uptake dysfunction following traumatic brain injury(TBI)are believed the crucial factors for the prognosis.The controlled cortex injury(CCI)model is constructed to investigate the effects of apolipoprotein E(apo E)mimetic peptide-COG1410 on motor function,brain edema,inflammatory response,angiogenesis and cerebral glucose uptake after TBI in the current study.Methods:The mice model of TBI was constructed by the controlled cortex impact devices and the C57BL/6J male mice were divided into 4 groups: the normal control group,the sham-operated group,the normal saline-treated group(the vehicle group)and the COG1410-treated group randomly.The animals in the COG1410-treated group were injected with apoE mimetic peptide—COG1410 every 24 hours via the tail vein after injury,and the saline injection therapy were used in the vehicle group.Rotarod test,Evans blue(EB)dye,dry-wet method,Enzyme-linked Immunosorbent Assay(ELISA),Immunohistochemistry,Bruker 7.0 Tesla preclinicalMRI and Inveon-micro-PET/CT were used to detect the motor dysfunction,the BBB permeability,the brain water content(BWC),the expression of vascular endothelial growth factor(VEGF)andinflammatory cytokine,angiogenesis,the volume of vascular cerebral edema and cerebral glucose uptake respectively after TBI.Results:1.ApoE mimetic peptide-COG1410 improved the motor dysfunction after CCI.CCI induced motor deficits compared with the sham-operated group and administration of COG1410 significantly improved motor deficits compared with the vehicle group over the 7 days testing period.Furthermore,the motor deficits reached the minimum for the two group treated with saline and COG1410 at 1 day after injury,and the COG1410-treated group returned the baseline while the vehicle group was still under the baseline at 7 days after injury.2.ApoE mimetic peptide-COG1410 reduced the brain edema after CCI.CCI resulted in the BBB disruption,which increased the BWC and the volume of vasogenic cerebral edema.Administration of COG1410 decreased the BBB disruption,and also reduced the BWC and the volume of vasogenic cerebral edema.3.ApoE mimetic peptide-COG1410 suppressed the expression of VEGF and angiogenesis after CCI.CCI increased the expression of VEGF at 1 day after injury and then it got to the peak at 3days.And CCI also induced the angiogenesis,but the angiogenesis was first observed at 3 days after injury.Administration of COG1410 significantly reduced the expression of VEGF and angiogenesis.Furthermore,there was a conspicuous difference in morphology between neovascularization after CCI and normal microvessels in the control group.And the neovascularization was line-like or bud-like,but thenormal microvessels were ring-shaped.4.ApoE mimetic peptideCOG1410 suppressed the expression of TNF-α.CCI increased the expression of TNF-α at 1 day after injury and the expression of TNF-αreturned the baseline at 3 days after injury.Administration of COG1410 significantly supressed the expression of TNF-α.5.ApoE mimetic peptide-COG1410 increased the cerebral glucose uptake after CCI.There was a transient reduction of glucose uptake in the peri-contusion and ipsilateral hemisphere of injury.Administration of COG1410 increased the glucose uptake of the peri-contusion and ipsilateral hemisphere of injury compared with the vehicle group.Conclusion: COG1410 significantly relieved the BBB disruption,inflammatory response,brain edema and improved cerebral glucose metabolism and motor deficits.These data suggest that COG1410 is a promising preclinical therapeutic agent for the treatment of TBI.