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

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.

Delayed inhibition of Nogo-A does not alter injury-induced axonal sprouting but enhances recovery of cognitive function following experimental traumatic brain injury in rats.

Traumatic brain injury causes long-term neurological motor and cognitive deficits, often with limited recovery. The inability of CNS axons to regenerate following traumatic brain injury may be due, in part, to inhibitory molecules associated with myelin. One of these myelin-associated proteins, Nogo-A, inhibits neurite outgrowth in vitro, and inhibition of Nogo-A in vivo enhances axonal outgrowth and sprouting and improves outcome following experimental CNS insults. However, the involvement of Nogo-A in the neurobehavioral deficits observed in experimental traumatic brain injury remains unknown and was evaluated in the present study using the 11C7 monoclonal antibody against Nogo-A. Anesthetized, male Sprague-Dawley rats were subjected to either lateral fluid percussion brain injury of moderate severity (2.5-2.6 atm) or sham injury. Beginning 24 h post-injury, monoclonal antibody 11C7 (n=17 injured, n=6 shams included) or control Ab (IgG) (n=16 injured, n=5 shams included) was infused at a rate of 5 microl/h over 14 days into the ipsilateral ventricle using osmotic minipumps connected to an implanted cannula. Rats were assessed up to 4 weeks post-injury using tests for neurological motor function (composite neuroscore, and sensorimotor test of adhesive paper removal) and, at 4 weeks, cognition was assessed using the Morris water maze. Hippocampal CA3 pyramidal neuron damage and corticospinal tract sprouting, using an anterograde tracer (biotinylated dextran amine), were also evaluated. Brain injury significantly increased sprouting from the uninjured corticospinal tract but treatment with monoclonal antibody 11C7 did not further increase the extent of sprouting nor did it alter the extent of CA3 cell damage. Animals treated with 11C7 showed no improvement in neurologic motor deficits but did show significantly improved cognitive function at 4 weeks post-injury when compared with brain-injured, IgG-treated animals. To our knowledge, the present findings are the first to suggest that (1) traumatic brain injury induces axonal sprouting in the corticospinal tract and this sprouting may be independent of myelin-associated inhibitory factors and (2) that post-traumatic inhibition of Nogo-A may promote cognitive recovery unrelated to sprouting in the corticospinal tract or neuroprotective effects on hippocampal cell loss following experimental traumatic brain injury.

Intrathecal and serum interleukin-6 and the acute-phase response in patients with severe traumatic brain injuries.

Patients with severe traumatic brain injury (TBI) show a profound acute-phase response. Because interleukin-6 (IL-6) is an important mediator of these pathophysiological changes, IL-6 levels were monitored in the cerebrospinal fluid (CSF) and serum of 20 patients with severe isolated TBI. All patients received indwelling ventricular catheters for intracranial pressure monitoring and for release of CSF when intracranial pressure exceeded 15 mmHg. CSF and blood samples were drawn daily for up to 14 days. The CSF/serum albumin ratio (QA) served as a parameter of blood brain barrier dysfunction. Differential blood counts as well as the acute-phase proteins C-reactive protein, alpha 1-antitrypsin, and fibrinogen were recorded. IL-6 was detected in all CSF samples and reached values of up to 31,000 pg/mL, while serum levels remained significantly lower (alpha < or = .01) and never exceeded 1,100 pg/mL the entire study period. A correlation between CSF and serum IL-6 was found initially after the trauma and corresponded to a severe dysfunction of the blood brain barrier (r = .637, p = .001). Maximum IL-6 concentrations in serum correlated with peak levels of acute-phase proteins (C-reactive protein, alpha 1-antitrypsin, and fibrinogen). With regard to blood cell count, an initial leukocytosis combined with a borderline lymphocytopenia was observed. Thrombocytes decreased to a subnormal level during the first few days, but reached supranormal numbers by the end of the study period. Our results show that the increase of IL-6 levels in CSF and serum is followed by a profound acute-phase response in patients with TBI. Because cytokine concentrations are significantly lower in serum compared with CSF, we hypothesize that IL-6 produced in the central nervous system may play a role in initiating the acute-phase response.