The Role Of TAK1Pathway In Traumatic Brain Injury

Title:Expression and distribution of TAK1after rat traumatic brain injuryObjective:In the present study, we mainly investigated the expression and cellular localization of TAK1and p-TAK1during traumatic brain injury.Methods:Adult male rats were randomly divided into the control group and TBI groups. After the induction of TBI the animals were randomly assigned into five groups:animals surviving brain trauma for1,3,6,12(each n=6), and24h (n=10). Sham-operated rats were used as control. Animals of the control group were killed for sample collection at6h after being sham operated.Results:Western blot detection showed that a significant increase of TAK1and p-TAK1expression in the cortex after TBI. Moreover, TBI induced TAK1redistribution both in neurons and astrocytes of the lesion boundary zone. Immunohistochemical evidence show that TAK1was mainly expressed around nuclei in the cortex of sham-operated rats. Consistent with the results obtained by western blot analysis, the expression of TAK1was increased24h after TBI, with the enhanced immunoreactivity of TAK1in the cell cytosol in the border zone adjacent to the cortical lesion.Conclusions:TBI increased TAK1expression in the lesion boundary zo-ne.Moreover, TBI induced TAK1redistribution both in neurons and astro-cytes of the lesion boundary zone. Part2Title:Effect of OZ on brain damage induced by traumatic brain injury in ratsObjective:The aim of this study was to examine the mechanisms of TAK1inhibitor OZ against brain injury following traumatic brain injury in the rat.Methods:The effects of specific inhibition of the TAK1pathway by OZ (intracer-ebroventricular injection at10min post-trauma) on histopathological and behavioral outcomes in rats were assessed at24h post injury. The concentrations of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were measured using enzyme-linked immunosorbent assay (ELISA). Neuronal apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). We also examined the transcription factors nuclear factor-κB (NF-κB) and activating protein-1(AP-1) activities by electrophoretic mobility shift assay (EMSA). The functional outcome was determined by beam-walking performance at Id,3d and7d post-injury. Tissue sections were stained with Cresyl Violet at7d post-injury.Results:The number of TUNEL-positive stained cells was diminished and neuronal survival and neurological function were improved with OZ treatment. Biochemically, the high dose of OZ significantly reduced the levels of TAK1and p-TAK1, further decreased NF-κB and AP-1activities and the release of inflammatory cytokines. In addition, we found that both10min and3h post-trauma OZ therapies could markedly improve neurological function and neuronal survival after long-term survival.Conclusions:These results revealed that the inhibitor OZ affords signi-ficant neuro-protection and amelioration of neurobehavioral deficits after experimental TBI, suggesting a potential rationale for manipulating this pathway in clinical practice. Part3Title:Expression and distribution of TAK1in Patients with traumatic brain injuryAbstractObjective:To evaluated the expression and distribution of TAK1in brain tissue of TBI patients.Methods:Contused brain tissue biopsies were obtained from4patients who receive surgery less than24hours after TBI. Immunohistochemistry was performed to ascertain the immuno-reactivity of TAK1. We also performed double immunofluorescent staining to evaluate the distribution of TAK1.Results:TAK1expression was significantly increased in human patients after TBI. Moreever, TAK1is expressed both in neurons and astrocytes in brain tissue of TBI patients.Conclusions:These data demonstrated that TAK1expression was significantly increased in human patients after TBI, and therapeutic targeting of the TAK1pathway may hold promise for future clinical applications.