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.
Habgood
M D
MD
Victorian Neurotrauma Research Group, Department of Pharmacology, Centre for Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia. mhabgood@unimelb.edu.au
Bye
N
N
Dziegielewska
K M
KM
Ek
C J
CJ
Lane
M A
MA
Potter
A
A
Morganti-Kossmann
C
C
Saunders
N R
NR
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001710:Biotin / Q000493:pharmacokinetics; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001930:Brain Injuries / Q000503:physiopathology*; D002199:Capillary Permeability / Q000502:physiology*; D004195:Disease Models, Animal; D006735:Horseradish Peroxidase / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors
D001798:Blood Proteins; D001710:Biotin; D006735:Horseradish Peroxidase