Protective Effects Of NRG1-ErbB4 Signaling On Traumatic Brain Injury And Its Underlying Mechanism

Traumatic Brain Injury(TBI)is a frequently-seen disease in neurosurgery with high mortaliy.Most of TBI survivors have high-degree disabilities,such as deficits in motor and cognitive functions,resulting in heavy spiritual and economic burdens for patients,their families and societies.Unfortunately,little is known about the pathogenesis and molecular mechanisms of TBI,and there is no effective treatment for TBI.Previous studies have shown that neuregulin1(NRG1),by binding to its specific receptor Erb B4,activates receptor tyrosine kinase activity and intracellular downstream signaling pathway in interneurons,inhibits the activity of excitatory neurons,and thus suppresses neuronal apoptosis induced by cerebral ischemia or other diseases.However,it is unclear if NRG1-Erb B4 signaling could have protective effects on TBI-induced neuronal damage.In the present study,we established a stable and reliable TBI animal model with internationally recognized methods,detected the expression levels of NRG1,Erb B4 and p Erb B4 in the TBI-induced injury region.The number of neurons and glial cells in the injury region were detected by immunohistochemistry.The tissue necrosis area and edema were also observed.NRG1 and the extracellular segment of Erb B4 were applied to the primary cortical neurons treated with glutamate,and the activity,mortality and death rate of CCK-8 cells were examined.GABA receptor antagonist or agonist was co-administered to see if the effects of NRG1 and the extracellular segment of Erb B4 were mediated via GABAergic interneurons.The experimental results are as below:1.TBI resulted in an increase in the expression of NRG1 and p Erb B4 but a decrease in the expression of Erb B4,and induced a decrease in neurons but an increase in astrocytes and microglia.2.Post-TBI mortality of Erb B4 knockout mice was significantly higher than that of wild-type mice,and the behavioral rehabilitation of Erb B4 knockout mice was also worse than that of wild-type mice.3.Erb B4 knockout mice demonstrated significantly larger necrotic area and more serious edema than wild type mice upon TBI.4.NRG1-Erb B4 signaling protects neurons from glutamate-induced damage,and such protective effect could be blocked by GABA receptor antagonist.However,GABA receptor agonist has no synergistic action with NRG1-Erb B4 signaling.The present results indicate that NRG1-Erb B4 signaling protects cortical neurons from TBI-induced damage,and such effect is probably mediated via promoting GABA release.