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Régina, Anthony; Demeule, Michel; Laplante, Alain; Jodoin, Julie; Dagenais, Claude; Berthelet, France; Moghrabi, Albert; Béliveau, Richard

doi:10.1023/a:1013104423154

Cited by 123 publications

(29 citation statements)

References 76 publications

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“…Further treatment of these tumours is difficult. Provided that the tumour does not disrupt the BBB, brain tumours are even intrinsically resistant to these drugs, as they are behind the BBB (Regina et al 2001). A combination of drugs including prednisolone, which are all Pgp substrates, may mutually increase their active brain levels by saturating Pgp.…”

Section: Discussionmentioning

confidence: 99%

The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

Karssen¹,

Meijer²,

Sandt³

et al. 2002

Journal of Endocrinology

102

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In the present study, we have investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in hampering the access of the synthetic glucocorticoid, prednisolone.In vivo, a tracer dose of [ 3 H]prednisolone poorly penetrated the brain of adrenalectomised wild-type mice, but the uptake was more than threefold enhanced in the absence of Pgp expression in mdr1a ( / ) mice. In vitro, in stably transfected LLC-PK1 monolayers the human MDR1 P-glycoprotein was able to transport prednisolone present at a micromolar concentration. A specific Pgp blocker, LY 335979, could block this polar transport of The ability of Pgp to export the synthetic glucocorticoid, prednisolone, suggests that uptake of prednisolone in the human brain is impaired, leading to a discrepancy between central and peripheral actions. Furthermore, the ensuing imbalance in activation of the two types of brain corticosteroid receptors may have consequences for cognitive performance and mood.

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Section: Discussionmentioning

confidence: 99%

The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

Karssen¹,

Meijer²,

Sandt³

et al. 2002

Journal of Endocrinology

102

View full text Add to dashboard Cite

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“…While the vessels in most brain tumors do not have a fully intact BBB and can be permeable, infiltrating cancer cells and small metastatic seeds are disseminated in the normal brain, where the normal brain blood vessels and the BBB prevent drug extravasation (66). Furthermore, it is known that tumor vasculature permeability is heterogeneous and that there are additional barriers to drug delivery, such as increased interstitial pressures (67) and efflux pumps (68,69). Major efforts have thus been undertaken to develop pharmaceuticals that circumvent the BBB, such as designing more lipid-soluble drugs, designing water-soluble drugs with high affinities for natural carriers at the BBB, or through the use of vectors such as amino acids and peptide carriers (70–72).…”

Section: Targeted Drug Deliverymentioning

confidence: 99%

Magnetic Resonance–Guided Focused Ultrasound

Jólesz

McDannold

2014

Neurologic Clinics

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“…Brain endothelial cells also express a multidrug resistance protein (e.g., P-glycoprotein, etc. ), which actively transports a variety of small molecules out of the cells [6]. Thus the BBB, this specialized vasculature of the CNS, functions to maintain the homeostatic environment of the brain.…”

Section: Blood-brain Barrier: the Major Target-ing Site For Anti-infementioning

confidence: 99%

Blood-brain Barrier Drug Discovery for Central Nervous System Infections

Jong

Huang²

2005

CDTID

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Central nervous system (CNS) infections are formidable diseases with high rates of morbidity and mortality. Since the majority of antimicrobial agents discovered so far do not cross the blood-brain barrier (BBB), the treatment of CNS infections is a major challenge issue. The development of drugs to treat those diseases requires consideration of achievable brain concentrations by targeting the following question. How can the chemistry and biology of the BBB, and infectomics be exploited for the development of drugs against CNS infections? To date drug targeting approaches, such as chemistry-based, biology-based, and infectomics-based, have been implicated in the development of drugs for treatment of CNS infections. The chemistry-based strategies rely on lipid-mediated BBB drug transport as substances that readily permeate the BBB. These usually include small molecular weight of lipophilic or hydrophobic molecules. The biology-based strategies depend on endogenous BBB transport systems, including carrier-mediated transport (CMT), active efflux transport (AET), and receptor-mediated transport (RMT). These transporters play important roles in the influxes and/or effluxes of drugs including antimicrobial agents in brain capillary endothelial cells that form the BBB. Both microbial and host signatures of infectomes, which can be dissected by infectomics, provide invaluable fountains in the search for novel antimicrobial therapies. Key markers associated with the mechanisms of neuronal injury may be identified, and thus, provide important targets for the prevention and treatment of CNS infections. This review focuses on the major BBB drug targeting strategies in the development of therapeutics for CNS infections. A combination of these strategies will ultimately lead to improved treatments.

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Untitled

Cited by 123 publications

References 76 publications

The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

Magnetic Resonance–Guided Focused Ultrasound

Blood-brain Barrier Drug Discovery for Central Nervous System Infections

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