Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications.
1. Osmotic opening of the blood-brain barrier by intracarotid infusion of a hypertonic arabinose or mannitol solution is mediated by vasodilatation and shrinkage of cerebrovascular endothelial cells, with widening of the interendothelial tight junctions to an estimated radius of 200 A. The effect may be facilitated by calcium-mediated contraction of the endothelial cytoskeleton. 2. The marked increase in apparent blood-brain barrier permeability to intravascular substances (10-fold for small molecules) following the osmotic procedure is due to both increased diffusion and bulk fluid flow across the tight junctions. The permeability effect is largely reversed within 10 min. 3. In experimental animals, the osmotic method has been used to grant wide access to the brain of water-soluble drugs, peptides, antibodies, boron compounds for neutron capture therapy, and viral vectors for gene therapy. The method also has been used together with anticancer drugs to treat patients with metastatic or primary brain tumors, with some success and minimal morbidity.
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Section on Brain Physiology and Metabolism, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. sir@helix.nih.gov
D000818:Animals; D001089:Arabinose / Q000008:administration & dosage / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D002339:Carotid Arteries; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006982:Hypertonic Solutions / Q000008:administration & dosage / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D008353:Mannitol / Q000008:administration & dosage / Q000494:pharmacology
D006982:Hypertonic Solutions; D008353:Mannitol; D001089:Arabinose