Radiation-induced blood-brain barrier damages: an in vitro study

A radiation-induced blood-brain barrier (BBB) breakdown has been supposed to explain the acute radiation syndrome and the delayed brain radiation injury, but it has been clearly demonstrated only at high doses. In a previous study (Diserbo et al., 2002), we showed that non-lethal total body irradiation produced an early transient increase in BBB permeability in rats but the underlying mechanisms of radiation-induced BBB breakdown remain unclear. In the present work, the effects of ionizing radiation were studied on an in vitro BBB model. Gamma irradiation induced an increase in [(14)C]-sucrose BBB permeability that can be detected 72 h after exposure at doses up to 4 Gy. This increase was more important 8 days after irradiation and could be limited by dexamethasone treatment. An increase in fluorescein and FITC-dextrans (4 kDa/70 kDa) permeability was also observed, which can be related to a substantial opening of endothelial cell tight-junctions but without massive modification of tight-junction protein (ZO-1, ZO-2, claudin-5, occludin) immunolabeling even 8 days after 25 Gy exposure. Formation of actin stress fibers occurred in endothelial cells 8 days after 25 Gy exposure. A progressive decrease in cellular density associated with a simultaneous spreading of the endothelial cells was also observed after irradiation. Anti-γH2AX immunolabeling was used to investigate both DNA double-strand break induction and repair rates in endothelial cells. It revealed long-lasting DNA double-strand breaks after gamma irradiation. A better understanding and awareness of these phenomena are essential for designing appropriate pharmacotherapy in radiation-therapy and treatment of accidental overexposure.