The Effect And Mechnism Of Cog1410 On Brain Edema And Glucose Uptake After Traumatic Brain Injury

BackgroundApolipoprotein E (APOE=gene, apoE=protein) is the major apolipoprotein expressed in the brain and it is not only involved in the lipid metabolism and cholesterol regulation in the nervous system, but also demonstrates obvious neuroprotective effect. Studies reported that, compared to wild mice, APOE knockout mice demonstrated more significant BBB damage, more severe increase of brain water content and more serious loss of neurological function after TBI. Intracerebroventricular injection of exogenous apoE alleviated neurofunction deficit after brain injury. However, due to the 34 kDa molecular weight of intact apoE holoprotein is too large to cross the BBB, which limits its clinical application. While, COG1410, a small apoE-mimetic peptides derived from the receptor-binding region of apoE were created that cross the BBB and retained neuroprotective properties of the apoE holoprotein. Several studies, including our previous research, have revealed that administration of COG1410 reduced the microglial activation, neuronal cell death, traumatic axonal injury and improved the neurofunction in animal models of TBI. But up to now, there is no report about the effect of COG1410 on the brain edema after TBI.In the present research, we assessed the effects of COG1410 on vasogenic brain edema and cytotoxic brain edema after TBI, and furtherly evaluated the effect of COG1410 on glucose uptake in the injured brain cortex after TBI.Objective To investigate the effects of apolipoprotein E mimetic peptide COG1410 on cerebral edema and the glucose uptake after TBI.Methods1. Evaluation of the effect of COG1410 on vasogenic brain edema after TBI. All of the in vitro BBB model were constructed by co-culture of primary astrocytes and cerebral microvascular endothelial cells. All BBB models were divided into normal group, oxygen glucose deprivation (OGD) group and ODG+COG1410 group. The permeability of BBB was investigated by detection of trans-epithelial electric resistance (TEER) and Evans blue (EB) permeability. The MMP-9 activity was detected by gelatinase and the expression of tight junction protein was detected by Western blot. Control cortical injury (CCI) was produced by PSI TBI-Device. Mice were randomly divided into normal group, sham injury group, TBI+saline group and TBI+COG1410 group.1 d and 3 d post-CCI is our research time point. Locomotor function of mice were detected by rotarod test. The permeability of BBB in the injured hemisphere were detected by EB content. Size of injured site and vasogenic brain edema were detected by T2WL The MMP-9 activity was detected by gelatinase and the expression of tight junction protein was detected by Western blot.2. Evaluation of the effect of COG1410 on cytotoxic brain edema after TBI. After construction of TBI model, mice were randomly divided into normal group, sham injury group, TBI+saline group and TBI+COG1410 group.1 d and 3 d post-CCI is our research time point. The expression of aquaporins 4 (AQP-4) in the pericontussion cortex was detected by RT-PCR, immunohistochemical and Western blot. The value of ADC in the pericontussion cortex was detected by DWI.3. Evaluation of the effect of COG1410 on glucose uptagke after TBI. After construction of TBI model, mice were randomly divided into normal group, TBI+saline group and TBI+COG1410 group.1 d and 3 d post-CCI is our research time point. The value of glucose uptagke in the injured cortex was detected by 18F-FDG Micro PET/CT.Results1. COG1410 reduced vasogenic brain edema after traumatic brain injury. After 1 h of OGD, the TEER of BBB decreased to the minimum value, but the permeability of EB was significantly increased. MMP-9 was activated and degradation of tight junction protein was significant. COG1410 significantly inhibited the increase of permeability of in vitro BBB model after OGD, inhibited MMP-9 activity and the degradation of tight junction protein. Locomotor function of mice obviously decreased in the acute stage of TBI. The permeability of EB increased in the injured hemisphere, as well as the increase of MMP-9 activity and degradation of tight junction protein. Administration of COG1410 markedly improve locomotor function of mice, reduced the BBB permeability, alleviated injured site and vasogenic brain edema, inhibited MMP-9 activity and degradation of tight junction protein on the 1 d and 3 d post-CCI.2. COG1410 reduced cytotoxic brain edema after traumatic brain injury. The expression of AQP-4 increased but the value of ADC decreased in the pericontussion cortex in the acute stage of TBI. Administration of COG1410 significantly inhibited over-expression of AQP-4 on the 1 d and 3 d post-CCI, inhibited the decrease of the value of ADC on the 3 d post-CCI.3. COG1410 improved glucose uptagke after traumatic brain injury. The uptake of 18F-FDG uptake in the injured cortex significantly decreased in the acute stage of TBI. Administration of COG1410 markedly improved the 18F-FDG uptake in the injured cortex on the Id and 3d post-CCI.ConclusionAdministration of COG1410 significantly inhibites vasogenic and cytotoxic brain, improves energy supply and improves the locomotor function of mice in the acute stage of TBI.