Brain endothelial cells form a continuous barrier which, with the help of specialized transport systems, selects the nutrients required for the brain to function properly. This blood-brain barrier (BBB) therefore plays a neuro-protective role by tightly controlling the access of substances to the brain. From the point of view of the treatment of brain tumours, however, this barrier constitutes a major obstacle in treating this type of cancer because it prevents pharmacological agents from reaching brain tissue.
To circumvent the therapeutic constraints imposed by the BBB, two principal lines of research are underway in our laboratory. First, we are examining the role of P-glycoprotein (P-gp), a protein involved in multi-drug resistance that is present in large quantities in brain capillaries. The molecular features of the action of P-gp are examined in detail in order to establish the biological functions of this protein in the capillaries that comprise the blood-brain barrier and to develop new ways to improve the effectiveness of chemotherapy treatments [1]. The competitive ability of a variety of endogenous hydrophobic substances such as progesterone, prostaglandins and leukotrienes with the drug transporter is also tested in order to identify the endogenous substances that interact with P-gp. Various agents that block the action of P-gp are also studied in our laboratory through an examination of the molecular interactions between these drugs and P-gp using BIAcore technology.
Second, we are endeavouring ourselves to identify new carriers that circumvent the restrictions imposed by the BBB and increase drug penetration in the brain. We recently demonstrated that the protein melanotransferrin considerably increases the transfer of chemotherapeutic molecules into brain tissue [1]. We are now characterizing this increased transcytosis by using a variety of in vivo and in vitro approaches including in situ brain perfusion and monolayer endothelial cells lines that mimic the BBB. The development of drug carriers is crucial in promoting the access of pharmacological agents to brain tissue and could have a major impact on several human pathologies of the CNS including brain tumours, Alzheimer's disease and other neurodegenerative diseases
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[1] Demeule M, Régina A, Annabi B, Bertrand Y, Bojanowski MW, Béliveau R. (2004) Brain endothelial cells as pharmacological targets in brain tumors. Mol Neurobiol. 30, 157-183.
[2] Demeule M, Poirier J, Jodoin J, Bertrand Y, Desrosiers RR, Dagenais C, Nguyen T, Lanthier J, Gabathuler R, Kennard M, Jefferies WA, Karkan D, Tsai S, Fenart L, Cecchelli R, Béliveau R. (2002) High transcytosis of melanotransferrin (P97) across the blood-brain barrier. J. Neurochem. 83, 924-933.
