β‐Caryophyllene protects in vitro neurovascular unit against oxygen‐glucose deprivation and re‐oxygenation‐induced injury

β‐Caryophyllene (BCP) mediates neuroprotection in cerebral ischemic animals. The neurovascular unit (NVU) acts as an intricate network to maintain the neuronal homeostatic microenvironment. However, the effects exerted by BCP on NVU remain unclear. Therefore, we established an in vitro NVU model to investigate the effects of BCP on oxygen‐glucose deprivation and re‐oxygenation (OGD/R)‐induced injury. This model involved the co‐culture of brain microvascular endothelial cells, neurons, and astrocytes. BCP (10 μmol/L) was applied for 24 h prior to OGD/R and maintained throughout OGD/R. Blood–brain barrier (BBB) integrity and neuronal apoptosis were analyzed. BCP pre‐treatment prior to the initiation of OGD/R significantly (i) decreased BBB permeability and neuronal apoptosis, (ii) mitigated oxidative stress damage and the release of inflammatory cytokines, (iii) down‐regulated Bax expression, metalloproteinase‐9 activity and expression, and (iv) up‐regulated claudin‐5, occludin, ZO‐1, growth‐associated protein‐43 and Bcl‐2 expression. Thus, BCP pre‐treatment exerted multiple protective effects on NVU in the context of OGD/R‐induced injury. These protective effects potentially occur via reductions in oxidative stress damage and inflammatory cytokines that induce BBB breakdown, subsequently resulting in reduced neuronal apoptosis. The NVU serves as putative therapeutic targets for cerebral ischemia, and the results of this study provide new insights for the application of BCP as a neuroprotective agent. β‐Caryophyllene (BCP) pre‐treatment exerts multiple protective effects on the neurovascular unit (NVU) in the context of oxygen‐glucose deprivation and re‐oxygenation (OGD/R)‐induced injury. These effects potentially result from the inhibition of blood–brain barrier breakdown as well as neuronal apoptosis via decreased oxidative stress damage and inflammation. The NVU thus is a putative therapeutic target for cerebral ischemia, and BCP is a promising therapeutic candidate to treat CNS disorders involving NVU damage.