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Drug resistance in brain diseases and the role of drug efflux transporters

Nature Reviews Neuroscience volume 6, pages 591–602 (2005)Cite this article

Key Points

  • Despite advances in therapies for brain diseases, many patients are resistant to drug treatment. The biological basis of drug resistance is not completely understood, but is likely to include insufficient drug penetration to the brain regions or brain cells involved in the disease, which are the target of drug therapy.

  • Drugs that are used to treat brain diseases must penetrate from the blood to their site of action. Drug uptake into the brain depends on various factors, including the involvement of the physical barriers presented by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (blood–CSF) barrier, and drug affinity for specific transport systems located at both of these interfaces.

  • Various drugs used in the treatment of brain disorders are substrates for drug efflux transporters in the BBB and blood–CSF barrier. These transporters include the product of the multidrug resistance 1 (MDR1, also known as ABCB1) gene, P-glycoprotein (Pgp), and several members of the multidrug resistance protein (MRP, also known as ABCC) family.

  • Such membrane drug transporters, which actively shuttle drugs across the cell membrane, thereby extruding these drugs from the cell, were first identified in chemotherapy-resistant cancer cells, but were subsequently also found in many healthy body tissues. They protect cells or tissues from the accumulation of lipophilic xenobiotics that would otherwise freely penetrate cell membranes.

  • In the CNS, such drug transport systems influence the brain disposition and efficacy of many pharmacological agents that are used to treat brain cancers, epilepsy, depression, schizophrenia, CNS-based pain, and bacterial or viral infections of the CNS. Multidrug transporters such as Pgp are, therefore, thought to be important in the mechanisms that underlie drug resistance in brain diseases.

  • Multidrug transporters can contribute to drug resistance by their constitutive expression in the BBB and blood–CSF barrier, thereby restricting the brain access of numerous drugs and enhancing drug extrusion from the brain, so that the concentrations of drugs in the brain cannot become sufficiently high for therapeutic efficacy. Furthermore, in some brain diseases, such as brain tumours, HIV and epilepsy, intrinsic or acquired overexpression of multidrug transporters in the BBB or brain target tissue limits drug penetration into that tissue.

  • The expression of drug efflux transporters in the brain is under tight transcriptional regulation by orphan nuclear receptors, such as the pregnane X receptor, but is also affected by environmental stimuli that evoke stress responses and by endogenous neurotransmitters, such as glutamate. Furthermore, polymorphisms in transporter genes can alter the expression and functionality of drug efflux transporters such as Pgp and might be involved in the drug resistance of brain diseases.

  • Modulating or bypassing such transporters at the BBB might be useful future strategies for improving drug therapy. Mechanisms by which efflux transporter activity in the BBB can be modulated include direct inhibition by specific inhibitors, functional modulation, and transcriptional modulation.

  • With respect to the ultimate proof of any resistance-mediating mechanism — showing that modulating the mechanism improves the tractability of the disease — different strategies, including inhibition of Pgp, are currently being evaluated in brain cancer and epilepsy. If these strategies prove successful, they will certainly be applied to other treatment-resistant brain diseases.

Abstract

Resistance to drug treatment is an important hurdle in the therapy of many brain disorders, including brain cancer, epilepsy, schizophrenia, depression and infection of the brain with HIV. Consequently, there is a pressing need to develop new and more effective treatment strategies. Mechanisms of resistance that operate in cancer and infectious diseases might also be relevant in drug-resistant brain disorders. In particular, drug efflux transporters that are expressed at the blood–brain barrier limit the ability of many drugs to access the brain. There is increasing evidence that drug efflux transporters have an important role in drug-resistant brain disorders, and this information should allow more efficacious treatment strategies to be developed.

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Figure 1: Multidrug transporters in the blood–brain barrier.
Figure 2: Schematic representation of the putative transmembrane structural organization of multidrug transporters.
Figure 3: P-glycoprotein and resistance to anticancer drugs.
Figure 4: Multidrug transporters and resistance to antiepileptic drugs.
Figure 5: P-glycoprotein expression in drug-resistant and drug-responsive epileptic rats.

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Acknowledgements

We are very grateful to D. S. Miller, G. Fricker, S. M. Sisodiya, C. E. Ribak and M. Gernert for their comments and constructive criticisms on an earlier draft of the manuscript and to M. M. Gottesman and G. Szakacs for thoughtful comments during the preparation of figure 2b. Furthermore, we would like to thank J. W. McAuley, M. A. Summers, J. L. Moore, L. Long and B. F. Shneker for sharing their unpublished observations. The authors' own work was supported by research grants from the Deutsche Forschungsgemeinschaft and the National Institute of Neurological Disorders and Stroke.

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  1. Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, and Center for Systems Neuroscience, Bünteweg 17, Hannover, D-30559, Germany

    Wolfgang Löscher & Heidrun Potschka

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Correspondence to Wolfgang Löscher.

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W.L. and H.P. are named as co-investors on a pending patent application (“Combination comprising a P-gp inhibitor and an antiepileptic drug”).

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DATABASES

Entrez Gene

BCRP

MRP1

MRP2

MRP4

Pgp

PXR

SXR

FURTHER INFORMATION

Löscher's laboratory

Löscher's homepage

ABC-transporter genes nomenclature

Glossary

XENOBIOTICS

Chemical substances that are foreign to a given organism. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides and various other compounds.

DRUG EFFLUX TRANSPORTERS

Membrane-integrated molecules that actively shuttle drugs across the cell membrane, thereby extruding these drugs from the cell. In the case of ABC transporters, transport is associated with the binding and hydrolysis of ATP.

ORPHAN NUCLEAR RECEPTORS

Receptors that have the structural features of known hormone receptors, but that lack identified ligands; assumed to mediate the effect of a potential ligand on gene expression.

PINOCYTOSIS

A cellular process that permits the active transport of extracellular fluid from the outside of a cell through the plasma membrane into the cell. In pinocytosis, tiny infoldings called caveolae (little caves) in the surface of the cell close and pinch off to form pinosomes, which are small fluid-filled vesicles that can move through the cell's cytoplasm and release their content by exocytosis.

GENETIC POLYMORPHISMS

Different variants of the same gene; frequency in the population ≥ 1%.

ANTIEPILEPTIC DRUG

(AED; also known as anticonvulsant drug). A drug that protects against the occurrence of epileptic seizures.

HIV PROTEASE INHIBITORS

A group of drugs used to reduce the viral load in patients with AIDS. The compounds act at the final stage of viral replication, and attempt to prevent the human immunodeficiency virus from making new copies of itself by interfering with the HIV protease enzyme.

RESISTANT

(Also know as refractory or intractable). Resistance to drug treatment is defined as the persistence of significant disease symptoms despite at least two treatment trials with drugs at the maximum tolerated doses for an adequate time period.

MICRODIALYSIS

Experimental procedure used to monitor the composition of the extracellular fluid of a specific tissue or organ in living animals or human patients.

BIPOLAR DISORDER

Manic-depressive illness that is characterized by excessive mood swings.

MAJOR DEPRESSIVE DISORDER

Mood disorder characterized by at least one severe depressive episode.

ATYPICAL ANTIPSYCHOTIC DRUGS

Second-generation antipsychotic drugs, such as clozapine, which are characterized by a reduced risk of extra-pyramidal side effects compared with first-generation ('typical') antipsychotic drugs.

POSITRON EMISSION TOMOGRAPHY

(PET). In vivo imaging technique used for diagnostic examination that involves the acquisition of physiological images based on the detection of positrons, which are emitted from a radioactive substance previously administered to the patient.

IMMUNOLIPOSOME

A spherical vesicle consisting of one or more concentric lipid bilayers enclosing one or more aqueous compartments that is coupled to an antibody. Immunoliposomes can mediate targeting to a specific tissue or organ. Drugs can be packed within the bilayer(s) or in the aqueous compartment(s).

NANOPARTICLES

Objects with a maximum feature size of 100 nm; used to pack drugs.

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Löscher, W., Potschka, H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 6, 591–602 (2005). https://doi.org/10.1038/nrn1728

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