Blood-brain barrier breakdown in traumatic brain injury: current insights and future directions

Traumatic brain injury (TBI) is among the most devastating condition and involves primary and secondary injury cascades. The blood-brain barrier (BBB) is a selective, semipermeable membrane that tightly controls the brain's microenvironment for proper neuronal function. Existing evidence demonstrates that TBI impairs the integrity and function of the BBB, leading to not only acute pathological changes but also long-term neuropathological consequences. Multiple BBB-related signaling molecules (e.g., Tie-2, EphB3, and Cav-1) are involved in the pathophysiological processes post-injury. These can result in microcirculatory insufficiency, neurotoxin accumulation, and cerebral edema after TBI. Together, such events synergistically cause axonal damage, neuronal cell death, and neuroinflammatory responses, which underlie the pathogenesis of TBI. In this review, we aim to summarize the pathophysiological roles of BBB breakdown in TBI, survey underlying mechanisms, and discuss therapeutic potential for this notorious disease by regulating the BBB.