Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier

Increasing evidence suggests that the soluble form of the β-amyloid peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease. Previously, we reported that treatment with certain antihypertensive dihydropyridine (DHP) compounds can mitigate Aβ production in whole cells and reduce brain Aβ burden in a mouse model of Alzheimer's disease. As Aβ clearance across the blood-brain barrier (BBB) is a key regulatory step in the deposition of Aβ in the brain, we examined the effect of DHP treatment on Aβ brain clearance. Treatment with certain DHP compounds significantly increased Aβ(1-42) transcytosis across the BBB in an in vitro model. The rank order of these compounds was nitrendipine>nicardipine=cilnidipine=lercanidipine>nimodipine>azelnidipine=nilvadipine. Conversely, amlodipine, felodipine, isradipine, and nifedipine had no effect on Aβ(1-42) BBB transcytosis. In an in vivo paradigm of Aβ clearance across the BBB, peripheral administration of nitrendipine, cilnidipine, and nilvadipine to wild-type animals facilitated the brain clearance of centrally administered exogenous Aβ(1-42), whereas with amlodipine, there was no effect. We also observed improved cognitive function in mice treated with nilvadipine following central Aβ(1-42) insult. Thus, in addition to the effect of certain DHP compounds on Aβ production, we demonstrate that certain DHP compounds also facilitate the clearance of Aβ across the BBB. This dual mechanism of action may be particularly effective in attenuating Aβ brain burden in Alzheimer's disease and could open the door to a new class of therapies for the treatment of this disease.     

P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood–brain barrier

The involvement of P-glycoprotein (P-gp) in buprenorphine (BNP) transport at the blood–brain barrier (BBB) in rats was investigated in vivo by means of both the brain uptake index technique and the brain efflux index technique. P-gp inhibitors, such as cyclosporin A, quinidine and verapamil, enhanced the apparent brain uptake of [³H]BNP by 1.5-fold. The increment of the BNP uptake by the brain suggests the involvement of a P-gp efflux mechanism of BNP transport at the BBB. [³H]BNP was eliminated with an apparent elimination half-life of 27.5 min after microinjection into the parietal cortex area 2 regions of the rat brain. The apparent efflux clearance of [³H]BNP across the BBB was 0.154 ml/min/g brain, which was calculated from the elimination rate constant (2.52 × 10^{? 2} min^{? 1}) and the distribution volume in the brain (6.11 ml/g brain). The efflux transport of [³H]BNP was inhibited by range from 32 to 64% in the presence of P-gp inhibitors. The present results suggest that BNP is transported from the brain across the BBB via a P-gp-mediated efflux transport system, at least in part.     

Efflux transport of[~3H]GABA across blood-brain barrier after cerebral ischemia-reperfusion in rats

目的：研究脑缺血／再灌后［３Ｈ］ＧＡＢＡ通过大鼠血脑屏障的外排转运是否增强及其机制．方法：将［３Ｈ］ＧＡＢＡ或ＧＡＢＡ（或丙磺舒）与其联合注射到缺血／再灌大鼠大脑皮层顶二区后，测定［３Ｈ］ＧＡＢＡ的脑外排指数（ＢＥＩ）及ｉｖ依文思蓝（ＥＢ）后ＥＢ的脑摄取量．结果：１０ｍｉｎ缺血／再灌３０ｍｉｎ、２ｈ、６ｈ和２４ｈ大鼠的ＢＥＩ分别为６７％，８３％，９２％和８７％，显著高于对照值（５８％），ＥＢ脑摄取量也显著增加；ＧＡＢＡ或丙磺舒明显降低正常及再灌６ｈ大鼠的ＢＥＩ，但对再灌５ｍｉｎ大鼠的ＢＥＩ无明显影响．结论：大鼠脑缺血／再灌后［３Ｈ］ＧＡＢＡ通过血脑屏障的外排转运显著增强．     

Improving the transport of chemotherapeutic drugs across the blood–brain barrier

The successful treatment of brain tumors or metastases in the brain is still hampered by the very efficient blood–brain barrier, which prevents the cerebral accumulation of a pharmacologically sufficient amount of a drug. Beside the possibility of disintegrating the functionality of this effective working barrier, a nanocarrier-mediated transport is presently an interesting and promising method to increase the drug concentration in the brain. Nanocarriers are small vesicles (<200 nm) and can be prepared by polymerization, resulting in nanoparticles, or by producing superficial lipid structures to incorporate the drug. In this context, liposomes are of importance owing to their ability to adapt their properties to the pharmacological requirements. In this article, we will give an overview of current possibilities of enhancing anticancer drug transport across the blood–brain barrier, based on its structure and functionality. Special consideration will be given to recent liposomal approaches that use active targeting for receptor-mediated transport across this physiological barrier.     

Nano carriers for drug transport across the blood–brain barrier

Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood–brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug–carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully discussed.     

Can nasal drug delivery bypass the blood-brain barrier?: questioning the direct transport theory

The connection between the nasal cavity and the CNS by the olfactory neurones has been investigated extensively during the last decades with regard to its feasibility to serve as a direct drug transport route to the CSF and brain. This drug transport route has gained much interest as it may circumvent the blood-brain barrier (BBB), which prevents some drugs from entering the brain. Approximately 100 published papers mainly reporting animal experiments were reviewed to evaluate whether the experimental design used and the results generated provided adequate pharmacokinetic information to assess whether the investigated drug was transported directly from the olfactory area to the CNS. In the analysis the large anatomical differences between the olfactory areas of animals and humans and the experimental conditions used were evaluated. The aim of this paper was to establish the actual evidence for the feasibility of this direct transport route in humans. Twelve papers presented a sound experimental design to study direct nose to CNS transport of drugs based on the authors' criteria. Of these, only two studies in rats were able to provide results that can be seen as an indication for direct transport from the nose to the CNS. No pharmacokinetic evidence could be found to support a claim that nasal administration of drugs in humans will result in an enhanced delivery to their target sites in the brain compared with intravenous administration of the same drug under similar dosage conditions.     

The role of β-blockers in the management of hypertension: An Asian perspective

Abstract

Following publication of the National Institute of Clinical Excellence (NICE) Guidelines in 2006, the use of β-blockers as first-line therapy in hypertension has been somewhat controversial. However, a recent reappraisal of the European Society of Hypertension guidelines highlights that these agents exhibit similar BP lowering efficacy to other classes of agents, prompting a re-examination of the utility of these agents in various patient populations. The authors felt that it is important to address this controversy and provide an Asian perspective on the place of β-blockers in current clinical practice and the benefits of β-blockade in selected patient populations. In addition to their use as a potential first-line therapy in uncomplicated hypertension, β-blockers have a particular role in patients with hypertension and comorbidities such as heart failure or coronary artery disease, including those who had a myocardial infarction. One advantage which β-blockers offer is the additional protective effects in patients with prior cardiovascular events. Some of the disadvantages attributed to β-blockers appear more related to the older drugs in this class and further appraisal of the efficacy and safety profile of newer β-blockers will lend support to the current guideline recommendations in Asian countries and encourage increased appropriate use of β-blockade in current clinical practice within Asia.     

The role of β-blockers in the management of hypertension: an Asian perspective

Following publication of the National Institute of Clinical Excellence (NICE) Guidelines in 2006, the use of β-blockers as first-line therapy in hypertension has been somewhat controversial. However, a recent reappraisal of the European Society of Hypertension guidelines highlights that these agents exhibit similar BP lowering efficacy to other classes of agents, prompting a re-examination of the utility of these agents in various patient populations. The authors felt that it is important to address this controversy and provide an Asian perspective on the place of β-blockers in current clinical practice and the benefits of β-blockade in selected patient populations. In addition to their use as a potential first-line therapy in uncomplicated hypertension, β-blockers have a particular role in patients with hypertension and comorbidities such as heart failure or coronary artery disease, including those who had a myocardial infarction. One advantage which β-blockers offer is the additional protective effects in patients with prior cardiovascular events. Some of the disadvantages attributed to β-blockers appear more related to the older drugs in this class and further appraisal of the efficacy and safety profile of newer β-blockers will lend support to the current guideline recommendations in Asian countries and encourage increased appropriate use of β-blockade in current clinical practice within Asia.     

The intriguing role of Rifaximin in gut barrier chronic inflammation and in the treatment of Crohn’s disease

Introduction: The gastrointestinal tract acts as a functional unit organized as a semipermeable multilayer system, in which commensal gut microbiota represents the anatomical barrier. Recently, several studies have highlighted the involvement of gut microbiota in inflammatory bowel diseases (IBD) pathogenesis, in sustaining gut barrier chronic inflammation, and in conditioning disease course and therapeutical response. This evidence provides a rationale for treating patients with gut microbiota modifiers. Among these, Rifaximin represents a non-traditional antibiotic able to act as a ‘eubiotic’ on intestinal barrier.

Area covered: The purpose of this narrative review is to explore the impact of Rifaximin on gut barrier and gut microbiota in IBD, in particular in Crohn’s disease (CD), and to analyze its potential therapeutic applications.

Expert opinion: The possibility of a beneficial activity of Rifaximin in chronic intestinal inflammation and CD has been debated and evaluated with different studies having obtained promising but still preliminary data. Larger trials are therefore needed. This gut-specific antibiotic could represent an alternative to systemic antibiotics thanks to its favorable safety profile and promising efficacy data. Rifaximin could exert, when appropriate, a synergic effect with immunomodulators in IBD, acting on both the microbial and the immunological sides of gut barrier impairment.     

Rapid regulation of the dopamine transporter: role in stimulant addiction?

Dopamine (DA) and the DA transporter (DAT) play important roles in psychomotor stimulant behavioral activation and reward. By understanding how DAT activity is regulated, we will better appreciate its contribution to normal neurotransmission and to brain diseases like drug addiction. DAT is regulated long-term by chronic drug administration. It is also regulated in a rapid, dynamic fashion by many factors--including brief exposure to DAT substrates, e.g. DA and amphetamine, and inhibitors, e.g. cocaine. We found that individual differences in the initial and sensitized locomotor responsiveness of rats to cocaine reflect differences in in vivo DAT function. Our ex vivo studies have further suggested that differences in basal and/or rapid cocaine-induced expression of functional DATs in striatum contribute to the differences in initial responsiveness. Studies in model systems have demonstrated that short-term DAT regulation occurs by altered transporter trafficking, and thereby cell surface expression. For example, a rapid, complex regulation of DAT by DA is suggested. Amphetamine causes DAT internalization into early endosomal compartments whereas cocaine appears to up-regulate surface expression of DAT. Future studies are needed to confirm these observations in neurons, as well as to elucidate the mechanisms of rapid DAT endocytic trafficking at neuronal synapses.     

The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood–brain barrier in sheep

Background and purpose:

The effect of age on the distribution of morphine and morphine-3-glucuronide (M3G) across the blood–brain barrier (BBB) was studied in a sheep model utilizing intracerebral microdialysis. The effect of neonatal asphyxia on brain drug distribution was also studied.

Experimental approach:

Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg·kg⁻¹, was intravenously administered as a 10 min constant infusion. Microdialysis and blood samples were collected for up to 360 min and analysed using liquid chromatography-tandem mass spectrometry. The half-life, clearance, volume of distribution, unbound drug brain : blood distribution ratio (K_p,uu) and unbound drug volume of distribution in brain (V_u,brain) were estimated.

Key results:

Morphine K_p,uu was 1.19 and 1.89 for the sheep and premature lambs, respectively, indicating that active influx into the brain decreases with age. Induced asphyxia did not affect transport of morphine or M3G across the BBB. Morphine V_u,brain measurements were higher in sheep than in premature lambs. The M3G K_p,uu values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups.

Conclusions and implications:

The morphine K_p,uu was above unity, indicating active transport into the brain; influx was significantly higher in premature lambs than in adult sheep. These results in sheep differ from those in humans, rats, mice and pigs where a net efflux of morphine from the brain is observed.     

Role of P-glycoprotein in restricting the brain penetration of tanshinone IIA,a major active constituent from the root of Salvia miltiorrhiza Bunge,across the blood–brain barrier

Tanshinone IIA (TSA) is a major constituent of Salvia miltiorrhiza Bunge widely used in the treatment of stroke. This current study aimed to investigate the nature of brain penetration of TSA using several in vitro and in vivo models. The uptake and efflux of TSA in primary rat brain microvascular endothelial cells (RBMVECs) were altered in the presence of a PgP inhibitor or multidrug-resistance-associated protein (Mrp1/2) inhibitor. A polarized transport of TSA was found in RBMVEC monolayers with facilitated efflux from the abluminal to the luminal side. The polarized transport of TSA was attenuated by PgP or Mrp1/2 inhibitors. In an in situ rat brain perfusion model, TSA crossed the blood–brain barrier at a greater rate than that for sucrose, and the brain penetration was increased in the presence of a PgP or Mrp1/2 inhibitor. The brain levels of TSA were only about 31% of that in the plasma and it increased to 74–77% of plasma levels when verapamil or quinidine was coadministered in rats. The entry of TSA to the central nervous system (CNS) significantly increased in rats subjected to middle cerebral artery occlusion or treatment with quinolinic acid. The normalized brain penetration of TSA in mdr1a^(?/?) mice was much higher than the wild-type mice. Taken collectively, these findings provide evidence that TSA has limited brain penetration through the blood–brain barrier owing to the contribution of PgP and possibly Mrp1/2.     

How significant is the role of P-glycoprotein in drug absorption and brain uptake?

Although P-glycoprotein (P-gp) is highly expressed in both intestinal epithelial cells and endothelial cells of brain capillaries, and functions as an efflux transporter in both organs, the impact of P-gp on intestinal absorption and brain uptake of drugs is quantitatively very different. The effect of P-gp on drug absorption is not quantitatively as important as suggested. Many drugs are good human P-gp substrates and yet exhibit reasonable oral bioavailability. In contrast, P-gp plays a quantitatively very important role in blocking the brain uptake of P-gp substrates. This review provides an overview of the role of P-gp in drug absorption and brain uptake, and explores possible factors that may explain the quantitative differences in the impact of P-gp on drug absorption and brain uptake.     

Assessment of ABCG2-mediated transport of xenobiotics across the blood–milk barrier of dairy animals using a new MDCKII in vitro model

The ATP-binding cassette (ABC) efflux transporter ABCG2 represents the main route for active secretion of drugs and toxins across the blood–milk barrier, thereby producing a potential health risk for dairy consumers through formation of relevant residues in milk. However, no suitable in vitro model is as yet available to systematically investigate ABCG2-mediated transport of xenobiotics into milk of dairy animals. We recently cloned ABCG2 from the lactating mammary gland of dairy cows (bABCG2) and goats (cABCG2). Thus, the objective of this study was to generate a suitable blood–milk barrier in vitro model using polarized MDCKII monolayers stably expressing mammary bABCG2 or cABCG2. ABCG2 protein was localized by confocal microscopy to the apical and lateral plasma membrane of polarized MDCKII cells. Intact barrier function of MDCKII-bABCG2 and MDCKII-cABCG2 monolayers was confirmed by determination of cell permeability of transcellular marker propranolol and paracellular marker atenolol which was ≤1 %. In flux assays, ABCG2 substrate 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) showed preferential basolateral to apical (B > A) transport in ABCG2-MDCKII cells. This apically directed PhIP transport was significantly inhibited by ABCG2 inhibitor fumitremorgin C (FTC) or the flavonoid equol. PhIP B > A transport in MDCKII-bABCG2 monolayers was additionally decreased by ABCG2 inhibitor Ko143. The fluoroquinolone antibiotic enrofloxacin was identified as a substrate of ruminant mammary ABCG2. The analgesic drug sodium salicylate was shown to be substrate of bABCG2 but not of cABCG2. Thus, the generated mammary ABCG2-expressing MDCKII cells represent a valuable tool to study active secretion of drugs and toxins into milk.     

Blood–brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein

According to in vitro studies the enantiomers of venlafaxine display different degrees of serotonin and noradrenaline reuptake inhibition. Therefore, clarification of the enantiomeric drug distribution between serum and brain is highly warranted. To elucidate if P-glycoprotein (P-gp) in a stereoselective manner transports venlafaxine and its metabolites out of the brain we used abcb1ab double-knockout mice that do not express P-gp. A single dose of racemic venlafaxine (10 mg/kg bw) was intraperitoneally injected to knockout (−/−) and wildtype (+/+) mice. Serum and brain samples were collected 1, 3, 6 and 9 h following drug administration for analysis by LC/MS/MS. One to six hours post-dose, the brain concentrations of venlafaxine, O-desmethylvenlafaxine and N-desmethylvenlafaxine were 2–3, 2–6 and 3–12 times higher in abcb1ab (−/−) mice compared to abcb1ab (+/+) mice, respectively. No major differences in the serum and brain disposition of the S- and R-enantiomers of venlafaxine and its metabolites were found between the groups. We conclude that P-gp decreases the penetration of the S- and R-enantiomers of venlafaxine and its major metabolites into the brain. No evidence of a stereoselective P-gp mediated transport of these substances was observed.