Julie Jodoin

High transcytosis of melanotransferrin (P97) across the blood–brain barrier

The blood–brain barrier (BBB) performs a neuroprotective function by tightly controlling access to the brain; consequently it also impedes access of proteins as well as pharmacological agents to cerebral tissues. We demonstrate here that recombinant human melanotransferrin (P97) is highly accumulated into the mouse brain following intravenous injection and in situ brain perfusion. Moreover, P97 transcytosis across bovine brain capillary endothelial cell (BBCEC) monolayers is at least 14‐fold higher than that of holo‐transferrin, with no apparent intra‐endothelial degradation. This high transcytosis of P97 was not related to changes in the BBCEC monolayer integrity. In addition, the transendothelial transport of P97 was sensitive to temperature and was both concentration‐ and conformation‐dependent, suggesting that the transport of P97 is due to receptor‐mediated endocytosis. In spite of the high degree of sequence identity between P97 and transferrin, a different receptor than the one for transferrin is involved in P97 transendothelial transport. A member of the low‐density lipoprotein receptor protein family, likely LRP, seems to be involved in P97 transendothelial transport. The brain accumulation, high rate of P97 transcytosis and its very low level in the blood suggest that P97 could be advantageously employed as a new delivery system to target drugs directly to the brain.

Drug transport to the brain: Key roles for the efflux pump P-glycoprotein in the blood-brain barrier

1. The blood-brain barrier (BBB) contributes to brain homeostastis and fulfills a protective function by controlling the access of solutes and toxic substances to the central nervous system (CNS). The efflux transporter P-glycoprotein (P-gp) is a key element of the molecular machinery that confers special permeability properties to the BBB. 2. P-gp, which was initially recognized for its ability to expel anticancer drugs from multidrug-resistant cancer cells, is strongly expressed in brain capillaries. Its expression in the BBB limits the accumulation of many hydrophobic molecules and potentially toxic substances in the brain. 3. The purpose of this review is to summarize the current state of knowledge about the expression of P-gp, its cellular localization as well as its possible functions in the BBB.

Dexamethasone modulation of multidrug transporters in normal tissues

The expression of P‐glycoprotein (P‐gp) and canalicular multispecific organic anion transporter (cMOAT or Mrp2) was evaluated by Western blotting analysis of rat tissues isolated following daily administration (1 mg kg−1 day−1) of dexamethasone over 4 days. Dexamethasone rapidly increased P‐gp expression more than 4.5‐ and 2‐fold in liver and lung, respectively, while it was decreased 40% in kidney. cMOAT expression was increased 2‐fold in liver and kidney following dexamethasone treatment. The levels of both proteins returned to control values by 6 days after the conclusion of dexamethasone administration. These results indicate that dexamethasone can modulate P‐gp and cMOAT expression in specific rat tissues and may have significant relevance for patients treated with dexamethasone as a single agent or in combination therapy with other drugs.

Green tea catechins as novel antitumor and antiangiogenic compounds.

The concept of cancer prevention by use of naturally occuring substances that could be included in the diet is under investigation as a practical approach towards reducing cancer incidence, and therefore the mortality and morbidity associated with this disease. Tea, which is the most popularly consumed beverage aside from water, has been particularly associated with decreased risk of various proliferative diseases such as cancer and atherosclerosis in humans. Various studies have provided evidence that polyphenols are the strongest biologically active agents in green tea. Green tea polyphenols (GTPs) mainly consist of catechins (3-flavanols), of which (-)-epigallocatechin gallate is the most abundant and the most extensively studied. Recent observations have raised the possibility that green tea catechins, in addition to their antioxidative properties, also affect the molecular mechanisms involved in angiogenesis, extracellular matrix degradation, regulation of cell death and multidrug resistance. This article will review the effects and the biological activities of green tea catechins in relation to these mechanisms, each of which plays a crucial role in the development of cancer in humans. The extraction of polyphenols from green tea, as well as their bioavailability, are also discussed since these two important parameters affect blood and tissue levels of the GTPs and consequently their biological activities. In addition, general perspectives on the application of dietary GTPs as novel antiangiogenic and antitumor compounds are also presented.

Multidrug resistance in brain tumors: Roles of the blood-brain barrier

Malignant brain tumors and brain metastases present a formidable clinical challenge against which no significant advances have been made over the last decade. Multidrug resistance (MDR) is one of the main factors in the failure of chemotherapy against central nervous system tumors. The MDR1 gene encoding P-glycoprotein (P-gp), a drug efflux pump which plays a significant role in modulating MDR in a wide variety of human cancers, is highly expressed in the blood–brain barrier (BBB). The BBB controls central nervous system exposure to many endogenous and exogenous substances. The exact molecular mechanisms by which the BBB is involved in the resistance of brain tumors to chemotherapy remain to be identified.The purpose of this review is to summarize reports demonstrating that P-gp, one of the most phenotypically important markers of the BBB, is present in primary brain tumors and thus plays a crucial role in their clinical resistance to chemotherapy.

P-glycoprotein in blood-brain barrier endothelial cells: Interaction and oligomerization with caveolins

P‐glycoprotein (P‐gp), an adenosine triphosphate (ATP)‐binding cassette transporter which acts as a drug efflux pump, is highly expressed at the blood–brain barrier (BBB) where it plays an important role in brain protection. Recently, P‐gp has been reported to be located in the caveolae of multidrug‐resistant cells. In this study, we investigated the localization and the activity of P‐gp in the caveolae of endothelial cells of the BBB. We used an in vitro model of the BBB which is formed by co‐culture of bovine brain capillary endothelial cells (BBCEC) with astrocytes. Caveolar microdomains isolated from BBCEC are enriched in P‐gp, cholesterol, caveolin‐1, and caveolin‐2. Moreover, P‐gp interacts with caveolin‐1 and caveolin‐2; together, they form a high molecular mass complex. P‐gp in isolated caveolae is able to bind its substrates, and the caveolae‐disrupting agents filipin III and nystatin decrease P‐gp transport activity. In addition, mutations in the caveolin‐binding motif present in P‐gp reduced the interaction of P‐gp with caveolin‐1 and increased the transport activity of P‐gp. Thus, P‐gp expressed at the BBB is mainly localized in caveolae and its activity may be modulated by interaction with caveolin‐1.