Changes in blood–brain barrier permeability to large and small molecules following traumatic brain injury in mice

Abstract

The entry of therapeutic compounds into the brain and spinal cord is normally restricted by barrier mechanisms in cerebral blood vessels (blood-brain barrier) and choroid plexuses (blood-CSF barrier). In the injured brain, ruptured cerebral blood vessels circumvent these barrier mechanisms by allowing blood contents to escape directly into the brain parenchyma. This process may contribute to the secondary damage that follows the initial primary injury. However, this localized compromise of barrier function in the injured brain may also provide a 'window of opportunity' through which drugs that do not normally cross the blood-brain barriers are able to do so. This paper describes a systematic study of barrier permeability in a mouse model of traumatic brain injury using both small and large inert molecules that can be visualized or quantified. The results show that soon after trauma, both large and small molecules are able to enter the brain in and around the injury site. Barrier restriction to large (protein-sized) molecules is restored by 4-5 h after injury. In contrast, smaller molecules (286-10,000 Da) are still able to enter the brain as long as 4 days postinjury. Thus the period of potential secondary damage from barrier disruption and the period during which therapeutic compounds have direct access to the injured brain may be longer than previously thought.

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

“…123 Because S100B does not cross the intact BBB, its levels in the serum (or a serum/CSF ratio) have been proposed to be an indicator of barrier integrity. To investigate this possibility, Kirchhoff et al 124 evaluated S100B in the serum of severe TBI patients to determine if its levels correlated with the presence of albumin in the CSF.…”

Involvement of Pro- and Anti-Inflammatory Cytokines and Chemokines in the Pathophysiology of Traumatic Brain Injury

“…Studies from our laboratory on a mouse model of focal TBI have recently demonstrated that at 1 to 2 h after injury there is extensive diffusion of intravenously injected horseradish peroxidase (a 40-kDa glycoprotein) in the pericontusional tissue, which by 4 h was no longer observed. 15 At 4 days post-injury, however, markers of smaller molecular weight (Ͻ10 kDa) continued to diffuse into the pericontusional cortex. Thus, the complete restoration of the barrier seems to require a time course that is much longer than that observed for large molecules.…”

Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury

“…Initial BBB opening in diffuse closed head injury is rapid and transient, beginning immediately after impact and closing within 30 min after impact 12 . However, there seems to be a size-selectivity issue at the BBB at sites of neural damage, during the early stages post-injury, with large molecules able to diffuse into the extravascular space in the short-term and smaller molecules able to diffuse for longer periods of time 13 . This has also been shown in cases of cytotoxic injury associated with the middle cerebral artery occlusion animal model of experimental stroke 14 .…”