Inflammation and blood-brain barrier (BBB) dysfunction are common features of different neuropathological conditions. Inflammatory cytokines and the excitotoxin glutamate contribute not only to neuronal damage, but to BBB opening in neurological diseases. The dysfunction of BBB further promotes neuroinflammation and brain pathologies thus forming a vicious circle. Our goal was to study BBB changes induced by kainate, a glutamate analog excitotoxin, and inflammatory cytokines on culture models of the BBB and investigate the protective effects of clinically used drugs, and natural compounds from grape. Kainate treatment directly damaged brain endothelial cells and significantly increased the permeability of the BBB model for marker molecules. The opening of the barrier was verified by the changed immunostaining pattern of tight junction proteins. Kainate stimulated the production of nitric oxide in brain endothelial cells. The antiinflammatory simvastatin and dexamethasone, and the antioxidant edaravone protected brain endothelial cells and preserved the barrier integrity. Dexamethasone attenuated the kainate-induced nitric oxide production by decreasing the iNOS/NOS2 mRNA expression. Natural phenolic compounds epicatechin, gallic acid and resveratrol, and the proanthocyanidin-rich grape seed extract were tested against cytokine-induced damages on a BBB model. We demonstrated that grape phenolic compounds protect cultured brain endothelial cells against tumor necrosis factor-α and interleukin-1β induced inflammation and oxidative stress through the NF-κB pathway. These data support the potential use of grape extracts and compounds in cardiovascular diseases. We successfully described the protective effects of clinically used drugs and grape natural compounds at the level of the BBB, which in the future may contribute to the treatment of diseases associated with BBB damage.