Brain-specific TRAF7 deletion ameliorates traumatic brain injury by suppressing MEKK3-regulated glial inflammation and neuronal death.

Neuronal death and neuroinflammation play critical roles in regulating the progression of traumatic brain injury (TBI). However, associated pathogenesis has not been fully understood. Tumor necrosis factor receptor-associated factor 7 (TRAF7), as the unique noncanonical member of the TRAF family, mediates various essential biological processes. Nevertheless, the effects of TRAF7 on TBI are still unclear. In this study, we showed that TRAF7 expression was markedly up-regulated in cortex and hippocampus of mice after TBI. Brain-specific TRAF7 deletion markedly ameliorated neuronal death in cortical and hippocampal samples of TBI mice, accompanied with cognitive impairments and motor dysfunction. Moreover, the aberrant activation of astrocyte and microglia in cortex and hippocampus of TBI mice was significantly restrained by TRAF7 conditional knockout in brain, as indicated by the increased expression of GFAP and Iba1. In addition, the releases of pro-inflammatory factors caused by TBI were also considerably diminished by brain-specific TRAF7 knockout, which were largely through the blockage of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. Importantly, mitogen-activated protein kinase kinase kinase 3 (MEKK3) expression levels were greatly enhanced in cortex and hippocampus of mice with TBI, while being dramatically ameliorated by TRAF7 knockout in brain. Mechanistically, we showed that TRAF7 directly interacted with MEKK3. Of note, MEKK3 over-expression almost abrogated the capacity of TRAF7 knockout to mitigate neuronal death and neuroinflammation in the isolated primary cortical neurons and glial cells upon oxygen-glucose-deprivation/reperfusion (OGD/R) stimulation. Collectively, TRAF7 may be an important molecular switch that leads to TBI in a MEKK3-dependent manner, and can be served as a therapeutic target for TBI treatment.

Effect of ranolazine postconditioning on the reperfusion injurysalvage kinase and mitochondrial permeability transition pore against ischemia-reperfusion injury in isolated rat heart / 中国药理学通报

Aim To investigate the effect of ranolazine postconditioning on myocardial apoptosis, the reperfusion injurysalvage kinase and the opening of MPTP in isolated rat hearts subjected to ischemia and reperfusion.Methods The langendorff mode was set up.Fifty-five SD rat hearts were randomly divided into 8 groups (n=7): ischema and reperfusion (I/R group),20 μmol·L~(-1) ranolazine postconditioning group(RPostC),ranolazine and the specific MPTP opener atractyloside group (RA), ranolazine and the specific ERK1/2 inhibitor PD98059 group (RP), ranolazine and the specific PI3K inhibitor PD98059 wortmannin group(RW), atractyloside group(A), PD98059 group (P) and wortmannin group (W). The isolated hearts were subjected to 30 minutes ischemia,10minutes drug postconditioning and 5 mitutes K-H buffer reperfusion.Myocardial apoptosis (TUNEL-positive cells), apoptotic index (AI), the opening of MPTP (spectrophotometry) and the The expression of p-AKT and p-ERK1/2 protein were measured at the end of reperfusion in each group.Results Compared with IR group, Myocardial AI and opening of MPTP were decreased in RPostC groups (P<0.05), the expression of p-AKT, p-ERK1/2 protein were increased in RPostC, RA, RP, and RW groups (P<0.05).There were no significant differences in other groups(P>0.05). Compared with RPostC group, Myocardial AI and opening of MPTP were increased in RA, RP, RW, A, P and W groups (P<0.05), and the expression of p-AKT、p-ERK1/2 protein were decreased in RP, RW, A, P and W groups (P<0.05). There were no significant differences of the expressions of p-AKT,p-ERK1/2 protein in RA groups (P>0.05). Compared with RA group, there were no significant differences in myocardial AI and opening of MPTP (P>0.05) and the expression of p-AKT and p-ERK1/2 protein were decreased in RP, RW, A, P and W groups (P<0.05).Conclusions Ranolazine postconditioning can attenuate myocardial apoptosis in isolated rat hearts subjected to ischemia and reperfusion via activation RISK pathway and inhibition of the opening of MPTP.