Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury

Abstract

Traumatic brain injury (TBI) is the leading cause of death in young adults and children. The treatment of TBI in the acute phase has improved substantially; however, the prevention and management of long-term complications remain a challenge. Blood-brain barrier (BBB) breakdown has often been documented in patients with TBI, but the role of such vascular pathology in neurological dysfunction has only recently been explored. Animal studies have demonstrated that BBB breakdown is involved in the initiation of transcriptional changes in the neurovascular network that ultimately lead to delayed neuronal dysfunction and degeneration. Brain imaging data have confirmed the high incidence of BBB breakdown in patients with TBI and suggest that such pathology could be used as a biomarker in the clinic and in drug trials. Here, we review the neurological consequences of TBI, focusing on the long-term complications of such injuries. We present the clinical evidence for involvement of BBB breakdown in TBI and examine the primary and secondary mechanisms that underlie such pathology. We go on to consider the consequences of BBB injury, before analyzing potential mechanisms linking vascular pathology to neuronal dysfunction and degeneration, and exploring possible targets for treatment. Finally, we highlight areas for future basic research and clinical studies into TBI.

Figure 1

Pathophysiological events in traumatic brain injury. Early symptoms of blood vessel and brain parenchyma compromise appear as blood flow irregularities and lead to metabolic imbalance, ischemia, hypoxia and excitotoxicity. Such processes, which are associated with breakdown of the blood–brain barrier, might lead directly to the induction of signaling cascades and complex interactions between pathological processes within the neurovascular unit. The result of these interactions is the formation of brain edema, a local inflammatory response and an increase in neuronal excitability. These early events might progress, interact and initiate acute complications, such as increased intracranial pressure, ischemic cell damage, seizures and death. In parallel, slower pathophysiological mechanisms, such as neovascularization, transformation and dysfunction of astrocytes, and changes in synaptic wiring, underlie the development of epilepsy, psychiatric and cognitive disabilities, and neurodegenerative pathologies such as Alzheimer disease.^,