Current Pharmaceutical Design - Volume 17, Issue 26, 2011

The delivery of pharmacological compounds to the injured brain is a huge challenge, which may predispose to drug failure and resistance. Besides the limited passage of drugs across the blood-brain barrier, which is a physical obstacle for the majority of pharmacological compounds, brain capillary cells express ATP-binding cassette (ABC) transporters on their surface, which actively remove drugs from the brain against concentration gradients. Eliminating a large number of pharmacological compounds and endogenous substrates from the brain tissue, ABC transporters play a major role for the maintenance of brain homeostasis and detoxification. The present issue summarizes current knowledge on ABC transporters in the injured brain, outlining how these efflux systems are regulated under pathological conditions, how they impede the brain accumulation of drugs and how they might contribute to the pathogenesis of neurological diseases once they become dysfunctional. This issue analyzes the validity of the concept of multidrug resistance, evaluating how ABC transporters may be modified in order to enable the development of more efficacious pharmacological treatments.

The neurovascular unit (NVU), consisting of endothelial cells, basement membrane, pericytes, astrocytes and microglial cells, couples local neuronal function to local cerebral blood flow and regulates transport of blood-borne molecules across the blood-brain barrier (BBB). The building blocks and the phenotype of the NVU are well-established but the intercellular signaling between the different components remains elusive. A better understanding of the cellular interactions and signaling within the NVU is critical for the development of efficient therapeutics for the treatment of a variety of brain diseases, such as brain cancer, stroke, neuroinflammation and neurodegeneration. This review gives an overview about the current in vivo knowledge of the NVU and the communication between its different cellular constituents. We also discuss the usefulness of various model organisms for studies of the brain vasculature.

Proper understanding of blood-brain barrier (BBB) regulation is crucial to reduce/prevent its disruption during injury. Since high brain complexity makes interpretation of in vivo data challenging BBB studies are frequently performed using simplified in vitro models. Although such models represent an important and frequently employed alternative for investigation of BBB function and alterations, our ability to translate in vitro findings to in vivo situation remains sub-optimal. Consequently, despite the fact that our knowledge of the cellular and molecular mechanisms underlying BBB physiology and pathophysiology is constantly increasing, our ability to modulate barrier function remains virtually non-existent. Classical in vitro model systems have provided a wealth of knowledge until now, but it is now evident that newer in vitro models that are more representative of the in vivo situation are needed to further our understanding of barrier physiology. This paper will provide an overview of the BBB cellular components and the most frequently used in vitro BBB model systems. I will discuss their advantages and disadvantages, as well as highlight recently developed models that more closely mimic the BBB in vivo.

According to the World Health Organization Central nervous system disorders are the major medical challenge of the 21st Century, yet treatments for many CNS disorders are either inadequate or absent. One reason is the existence of the blood-brain barrier, which strictly limits the access of substances to the brain. A key element of the barrier function is the expression of ABC export proteins in the luminal membrane of brain microvessel endothelial cells. Understanding the signaling cascades and the response to endogenous and exogenous stimuli, which lead to altered expression or function of the transporters as well as subsequent modulation of the transporters, may offer novel strategies to overcome the barrier and to improve drug delivery to the brain. This review gives a short overview about structure of the key elements of the blood-brain barrier with emphasis on ABC transporters. An insight into regulation of function and expression of these transport proteins is given and the involvement of these transporters in CNS diseases is discussed.

Protection of the brain is strengthened by active transport and ABC transporters. P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a substrate from the brain, which is important for maintaining loco-regional homeostasis in the brain and protection against toxic compounds. Importantly, dysfunctional BBB P-gp transport is postulated as an important factor contributing to accumulation of aggregated protein in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, P-gp is a major factor in mediating resistance to brain entry of numerous exogenous compounds, including toxins that can be involved in PD pathogenesis. This review highlights the role of altered P-gp function in the pathogenesis and progression of neurodegenerative disease. Also the implications of alterations in P-gp function for the treatment of these diseases are discussed.

The blood-brain barrier (BBB) protects the brain against endogenous and exogenous compounds and plays an important part in the maintenance of the microenvironment of the brain. In particular, the importance of brain-to-blood transport of brain-derived metabolites across the BBB has gained increasing attention as a potential mechanism in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, which is characterized by the aberrant polymerization and accumulation of specific misfolded proteins, particularly β-amyloid (Aβ). There is growing evidence that the ABC transport protein P-glycoprotein (P-gp), a major component of the BBB, mediates the efflux of Aβ from the brain. In this review, we discuss the possible role of P-gp in Alzheimer's disease and other neurodegenerative disorders, and consider how a fuller understanding of this function might promote the development of more effective treatment strategies.

Ischaemic stroke is one of the most common diseases world-wide. Recent studies provide new insights into the role of ATPbinding cassette (ABC) transporters in brain ischaemia. Expressional and functional transporter changes that have been observed at the brain capillary endothelium during ischaemia impede the access of pharmacological compounds into the brain tissue. The current review summarizes the most important findings and discusses the role of hypoxia, inflammation, oxidative stress and lipids as factors regulating ABC transporters at the blood-brain barrier. A better understanding of biodistribution processes at the blood-brain barrier is urgently needed, so that the accumulation of drugs in the brain can be improved, enabling a successful translation of pharmacological treatments in ischaemic stroke.

Brain cancer is a devastating disease. Despite extensive research, treatment of brain tumors has been largely ineffective and the diagnosis of brain cancer remains uniformly fatal. Failure of brain cancer treatment may be in part due to limitations in drug delivery, influenced by the ABC drug efflux transporters P-gp and BCRP at the blood-brain and blood-tumor barriers, in brain tumor cells, as well as in brain tumor stem-like cells. P-gp and BCRP limit various anti-cancer drugs from entering the brain and tumor tissues, thus rendering chemotherapy ineffective. To overcome this obstacle, two strategies - targeting transporter regulation and direct transporter inhibition - have been proposed. In this review, we focus on these strategies. We first introduce the latest findings on signaling pathways that could potentially be targeted to down-regulate P-gp and BCRP expression and/or transport activity. We then highlight in detail the new paradigm of P-gp and BCRP working as a “cooperative team of gatekeepers” at the blood-brain barrier, discuss its ramifications for brain cancer therapy, and summarize the latest findings on dual P-gp/BCRP inhibitors. Finally, we provide a brief summary with conclusions and outline the perspectives for future research endeavors in this field.

Owing to therapeutic progress, the role of ABC-transporters in infectious and autoimmune inflammatory CNS-diseases has recently gained considerable attention. In HIV-encephalitis and HIV-associated neurocognitive disorders, ABC-transporters are discussed to contribute to limited CNS-penetration and -retention of antiviral agents. In multiple sclerosis and its animal model experimental autoimmune encephalomyelitis, ABC-transporters may be involved in pathogenesis and treatment response alike. A prospective pharmacogenetic study is currently underway to examine the predictive role of genetic variations in ABC-transporters for treatment response and adverse events to mitoxantrone, a therapeutic agent used in aggressive MS. These approaches may aid in individualized treatment with this cytostatic anthracenedione, addressing its narrow therapeutic index with potentially fatal side effects. Finally, understanding regulation and function of ABC-transporters under inflammatory conditions may also optimize ABC-transporter-related treatment strategies in other neurological diseases (e.g. neurodegenerative, and neurovascular) where neuroinflammatory mechanisms have gained considerable attention as important contributors to pathogenesis.

Resistance to multiple antiepileptic drugs (AEDs) is a common problem in epilepsy, affecting at least 30% of patients. One prominent hypothesis to explain this resistance suggests an inadequate penetration or excess efflux of AEDs across the blood-brain barrier (BBB) as a result of overexpressed efflux transporters such as P-glycoprotein (Pgp), the encoded product of the multidrug resistance- 1 (MDR1, ABCB1) gene. Pgp and MDR1 are markedly increased in epileptogenic brain tissue of patients with AED-resistant partial epilepsy and following seizures in rodent models of partial epilepsy. In rodent models, AED-resistant rats exhibit higher Pgp levels than responsive animals; increased Pgp expression is associated with lower brain levels of AEDs; and, most importantly, co-administration of Pgp inhibitors reverses AED resistance. Thus, it is reasonable to conclude that Pgp plays a significant role in mediating resistance to AEDs in rodent models of epilepsy - however, whether this phenomenon extends to at least some human refractory epilepsy remains unclear, particularly because it is still a matter of debate which AEDs, if any, are transported by human Pgp. The difficulty in determining which AEDs are substrates of human Pgp is mainly a consequence of the fact that AEDs are highly permeable compounds, which are not easily identified as Pgp substrates in in vitro models of the BBB, such as monolayer (Transwell® ) efflux assays. By using a modified assay (concentration equilibrium transport assay; CETA), which minimizes the influence of high transcellular permeability, two groups have recently demonstrated that several major AEDs are transported by human Pgp. Importantly, it was demonstrated in these studies that Pgp-mediated transport highly depends on the AED concentration and may not be identified if concentrations below or above the therapeutic range are used. In addition to the efflux transporters, seizure-induced alterations in BBB integrity and activity of drug metabolizing enzymes (CYPs) affect the brain uptake of AEDs. For translating these findings to the clinical arena, in vivo imaging studies using positron emission tomography (PET) with 11C-labelled AEDs in epileptic patients are under way.

Some of the ATP-binding cassette (ABC) transporters like P-glycoprotein (P-gp; ABCB1, MDR1), BCRP (ABCG2) and MRPs (ABCCs) that are present at the blood-brain barrier (BBB) influence the brain pharmacokinetics (PK) of their substrates by restricting their uptake or enhancing their clearance from the brain into the blood, which has consequences for their CNS pharmacodynamics (PD). Opioid drugs have been invaluable tools for understanding the PK-PD relationships of these ABC-transporters. The effects of morphine, methadone and loperamide on the CNS are modulated by P-gp. This review examines the ways in which other opioid drugs and some of their active metabolites interact with ABC transporters and suggests new mechanisms that may be involved in the variability of the response of the CNS to these drugs like carrier-mediated system belonging to the solute carrier (SLC) superfamily. Exposure to opioids may also alter the expression of ABC transporters. P-gp can be overproduced during morphine treatment, suggesting that the drug has a direct or, more likely, an indirect action. Variations in cerebral neurotransmitters during exposure to opioids and the release of cytokines during pain could be new endogenous stimuli affecting transporter synthesis. This review concludes with an analysis of the pharmacotherapeutic and clinical impacts of the interactions between ABC transporters and opioids.

Polymorphisms in the drug transporter gene ABCB1 account for differences in the clinically efficacy of the most drugs, most likely by influencing their access to the brain. The majority proportion of depressed patients, given a regular dose, do not respond properly or experience severe side effects. One explanation may be the polymorphisms in the drug transporter gene ABCB1, which account for differences in the clinical efficacy of antidepressants, neuroleptics or mood stabilizers most likely by influencing their access to the brain. If patients are treated with a substrate of P-gp, functionally relevant genetic variants in the ABCB1 transporter could influence intracerebral drug concentrations and, thereby, clinical response. The review shows recently investigated clinical impact of ABCB1 variants including the three most important SNPs rs1045642, rs2032582, and rs2032583. In the paper, with respect not to go beyond the scope of this review, we will focus on these three SNPs. The final goal of pharmacogenetics is to help clinicians to choose the best treatment for each individual patient. From the evidence reviewed in this publication, it is likely that combination of metabolizing and drug target polymorphisms will produce the best prediction for the selection of the optimal dose and optimal drug as a function of the individual' s genetic profile.