Neuroprotectant androst-3 beta, 5 alpha, 6 beta-triol suppresses TNF-alpha-induced endothelial adhesion molecules expression and neutrophil adhesion to endothelial cells by attenuation of CYLD-NF-kappa B pathway

摘要

Neuroinflammation is one of key pathologic element in neurological diseases including stroke, traumatic brain injury, Alzheimer' s Disease, Parkinson's Disease, and multiple sclerosis as well. Up-regulation of endothelial adhesion molecules, which facilitate leukocyte adhesion to the endothelium, is the vital process of endothelial cells mediated neuroinflammation. Androst-3 beta, 5 alpha, 6 beta-triol (Triol) is a synthetic steroid which has been reported to have neuroprotective effects in hypoxia/re-oxygenation-induced neuronal injury model. In the present study, we firstly investigated whether Triol inhibited the TNF-alpha-induced inflammatory response in rat brain microvascular endothelial cells (RBMECs). Our data showed that Triol decreased TNF-alpha-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and the adhesion of neutrophil to RBMECs. We also found that Triol inhibited TNF-alpha-induced degradation of I kappa B alpha and phosphorylation of NF-kappa Bp65 that are required for NF-kappa B activation. Furthermore, Triol significantly reversed TNF-a-induced down-expression of CYLD, which is a deubiquitinase that negatively regulates activation of NF-kappa B. These results suggest that Triol displays an anti-inflammatory effect on TNF-a-induced RBMECs via downregulating of CYLD-NF-kappa B signaling pathways and might have a potential benefit in therapeutic neuroinflammation related diseases. (C) 2017 Elsevier Inc. All rights reserved.