Synergistic Neuroprotective Effects of Taurine and Tauroursodeoxycholic Acid on the Neurovascular Unit in Hypoxia-Reoxygenation Injury

Taurine and tauroursodeoxycholic acid are used for treating cerebral ischemia. In this study, we used the combination of taurine and tauroursodeoxycholic acid to establish a model of ischemia-reperfusion injury and evaluate the effect and target of the drug combination using the neurovascular unit (NVU) model of hypoxia and reoxygenation in vitro. Results showed that the combined application of these two drugs improved the survival of neurons, astrocytes, and endothelial cells; reduced inflammatory damage, levels of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1β, oxidative stress response, and the release of malondialdehyde and nitric oxide; and enhanced the activity of superoxide dismutase. Simultaneously, they acted on the blood-brain barrier (BBB) and improved the transendothelial electrical resistance value, reduced lactate dehydrogenase levels, improved the activity of γ-glutamyl transferase, and protected the integrity of the BBB against damage caused by oxygen-glucose deprivation/reoxygenation. At the same time, they prevented neuronal apoptosis, reduced the expression of Bax and caspase-3, and increased the expression of Bcl-2. These two drugs regulated the expression of connexin 43 (CX43) and aquaporin 4 (AQP4) in astrocytes, reducing the level of AQP4, and improving the activity of CX43. In addition, the drug combination increased the expression of tight junction proteins in endothelial cells, such as zona occludens-1, occluding, and claudin-5, and decreased the expression of matrix metalloproteinase (MMP)2 and MMP9. Furthermore, they acted together on the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and the addition of the p38 inhibitor SB203580 partially inhibited the expression of p38MAPK. Thus, the combined action of these drugs protected the NVU.