Osmotic opening of tight junctions in cerebral endothelium

Abstract

Hyperosmotic solutions of 3 M urea, either infused into one internal carotid artery or applied topically to the pia mater of rabbits, results in the opening of endothelial tight junctions through which horseradish peroxidase passes from blood to extracellular fluid of the brain. The evidence for this opening of the blood-brain barrier to protein is the entry of peroxidase into the extracellular pools between successive tight junctions. In animals not receiving 3 M urea, the interjunctional pools are inaccessible to proteins. Having passed through the endothelial junctions, the peroxidase spreads along the extracellular channels of the perivascular neuropil for approximately 100 P in 90 seconds. Most of the affected vessels are capillaries, though larger vessels are rendered leaky as well. Calyciform cisterns, that lie beneath shallow notches in the endothelium of untreated rabbits, appear to be enlarged after the administration of 3 M urea. It is undetermined whether these few endothelial cisterns and vesicles are involved in carrying protein from blood to the cerebral extracellular fluid.The injection into the internal carotid artery or pial application of solutions containing hyperosmolar concentrations of various substances causes a reversible opening of the blood-brain barrier in rab-

Recent Advances in Blood–Brain Barrier Disruption as a CNS Delivery Strategy

“…Moreover, multi-drug resistance (MDR) gene products, such as the P-gp efflux pump, are also illustrated as they are integral to the mechanism of the barrier. The osmotic BBBD procedure induces a retraction in the cell membrane, and a physical opening b accompanied by a modification of the Ca 2+ metabolism in the cell successfully visualized opened endothelial tight junctions with electron miscroscopy after intra-carotid infusion of mannitol in several species (32). In 1984, Dorovini-zis et al also observed opened inter-endothelial tight junctions when endothelial cell cultures were exposed to a hypertonic solution (33).…”

“…Since Evans Blue, which binds to albumin, is not expected to permeate through the intact BBB, this observation suggested a BBB alteration by hypertonic arabinose. The authors proposed that hypertonic solutions increased BBB permeability by inducing the shrinkage of cerebrovascular endothelial cells, thus producing a disruption of inter-endothelial tight junctions (31,32). The concept of osmotic BBBD was then introduced.…”

Structural Changes in the Rat Brain After Carotid Infusions of Hyperosmolar Solutions: A Light Microscopic and Immunohistochemical Study

“…Cerebral consequences of carotid infusions of hyperosmolar solutions have previously been studied in acute experiments with physiological and chemical methods (Rapoport et al, l970,1972a(Rapoport et al, l970, , 1972bl973,1977,1981a, 1981bBrightman et al, 1973;Ohno, Fredericks & Rapoport, 1979;Bullard, Bourdon & Bigner 1984). Transient changes may occur as reflected by alterations in uptake and metabolism of glucose, and in changes of local cerebral blood flow (Pappius et al, 1979;Rapoport, 1978;Rapoport et al, 1981aRapoport et al, , 1981bBeck et al, 1984).…”

“…For obvious reasons this should be carried out without causing unwanted brain damage in itself. Rapoport and coworkers have developed a method for transient opening of the BBB by intracarotid infusion of hyperosmolar solutions such as mannitol and urea (Rapoport, 1970;Rapoport, Bachman & Thompson, 1972a;Rapoport, Hori & Klatzo 1972b;Rapoport & Thompson, 1973;Brightman et al, 1973;Rapoport et al, 1977;Rapoport, Ohata & London, 1981a;Rapoport et al, 1981b). Drug entry and uptake into the brain parenchyma can in this way be increased (cf., Tomiwa, Hazama & Mikawa, 1983;Inoue et al, 1987) and the method has been tried in clinical situations as well, mainly to enhance the uptake of chemotherapeutic agents in the treatment of malignant brain tumours (Neuwelt et al, 1980(Neuwelt et al, , 1981(Neuwelt et al, , 1986(Neuwelt et al, , 1987Suda, Nakasu & Saito, 1985).…”

From polymeric particles to multifunctional nanocapsules for biomedical applications using the miniemulsion process

“…After the ''normal'' concentration of urea or mannitol in the blood is regained after several hours, the cells reobtain their initial size resulting in sealing the BBB again. 147,148 A chemical modification of the drug molecules (''prodrugs'') can also result in an enhanced BBB permeation. 145,149,150 It is also known that some types of polymeric nanoparticles in combination with surface characteristics are allowed to pass the brain.…”