Inhibition of transforming growth factor beta-activated kinase 1 confers neuroprotection after traumatic brain injury in rats

Abstract

The transforming growth factor beta-activated kinase 1 (TAK1), a member of the Mitogen-activated protein kinase kinase kinase family, is characterized as a key regulator in inflammatory and apoptosis signaling pathways. The aim of the present study was to evaluate the role of the TAK1 pathway in experimental traumatic brain injury (TBI) in rats. Adult male Sprague-Dawley rats were subjected to TBI using a modified Feeney's weight-drop model. The time course showed that a significant increase of TAK1 and p-TAK1 expression in the cortex after TBI. Moreover, TBI induced TAK1 redistribution both in neurons and astrocytes of the lesion boundary zone. The effects of specific inhibition of the TAK1 pathway by 5Z-7-oxozeaenol (OZ, intracerebroventricular injection at 10min post-trauma) on histopathological and behavioral outcomes in rats were assessed at 24h post injury. 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 TAK1 and p-TAK1, further decreased nuclear factor-κB and activator protein 1 activities and the release of inflammatory cytokines. In addition, we found that both 10min and 3h post-trauma OZ therapies could markedly improve neurological function and neuronal survival after long-term survival. These results revealed that the TAK1 pathway is activated after experimental TBI and the inhibitor OZ affords significant neuro- protection and amelioration of neurobehavioral deficits after experimental TBI, suggesting a potential rationale for manipulating this pathway in clinical practice.