Pain and the blood–brain barrier: obstacles to drug delivery

Advanced Drug Delivery Reviews 55 (2003) 987–1006 www.elsevier.com / locate / addr

Pain and the blood–brain barrier: obstacles to drug delivery Anne M. Wolka, Jason D. Huber, Thomas P. Davis* Department of Pharmacology, University of Arizona College of Medicine, P.O. Box 245050, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA Received 18 April 2003; accepted 8 May 2003

Abstract Delivery of drugs across the blood–brain barrier has been shown to be altered during pathological states involving pain. Pain is a complex phenomenon involving immune and centrally mediated responses, as well as activation of the hypothalamic–pituitary–adrenal axis. Mediators released in response to pain have been shown to affect the structure and function of the blood–brain barrier in vitro and in vivo. These alterations in blood–brain barrier permeability and cytoarchitecture have implications in terms of drug delivery to the central nervous system, since pain and inflammation have the capacity to alter drug uptake and efflux across the blood–brain barrier. An understanding of how blood–brain barrier and central nervous system drug delivery mechanisms are altered during pathological conditions involving pain and / or inflammation is important in designing effective therapeutic regimens to treat disease.  2003 Elsevier B.V. All rights reserved. Keywords: Inflammation; CNS response; HPA axis; Inflammatory mediator; Permeability; Transport

Contents 1. Introduction ............................................................................................................................................................................ 2. Function and structure of the blood–brain barrier in health ......................................................................................................... 3. Drug delivery across the blood–brain barrier in health ............................................................................................................... 3.1. Diffusion ......................................................................................................................................................................... 3.2. Carrier-mediated transport ................................................................................................................................................ 3.3. Endocytosis ..................................................................................................................................................................... 3.4. Drug efflux ...................................................................................................................................................................... 4. Pain mechanisms..................................................................................................................................................................... 4.1. Immune and central nervous system responses ................................................................................................................... 4.1.1. Cytokines and chemokines...................................................................................................................................... 4.1.2. Cellular adhesion molecules.................................................................................................................................... 4.1.3. Matrix metalloproteinases ....................................................................................................................................... 4.1.4. Kinins ................................................................................................................................................................... 4.1.5. Prostaglandins........................................................................................................................................................ 4.1.6. Excitatory peptides and amino acids ........................................................................................................................ *Corresponding author. Tel.: 1 1-520-626-7643; fax: 1 1-520-626-4053. E-mail address: [email protected] (T.P. Davis). 0169-409X / 03 / $ – see front matter  2003 Elsevier B.V. All rights reserved. doi:10.1016 / S0169-409X(03)00100-5

988 988 989 989 989 989 990 991 991 992 992 993 993 993 994

988

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

4.2. Activation of the hypothalamic–pituitary–adrenal axis ....................................................................................................... 5. Alterations of the blood–brain barrier by pain mediators ............................................................................................................ 5.1. Effects of proinflammatory mediators on the blood–brain barrier......................................................................................... 5.2. Effects of excitatory peptides and amino acids on the blood–brain barrier ............................................................................ 5.3. Effects of hypothalamic–pituitary–adrenal axis activation on the blood–brain barrier ........................................................... 6. Implications of pain responses in central nervous system drug delivery ....................................................................................... 6.1. Influence of increased blood–brain barrier paracellular permeability on drug delivery to the brain ......................................... 6.2. Influence of altered blood–brain barrier endocytosis on drug delivery to the brain ................................................................ 6.3. Potential influence of altered blood–brain barrier efflux on drug delivery to the brain ........................................................... 6.4. Potential influence of pain-induced glutamate release on the delivery of glutamate-conjugated drugs to the brain .................... 6.5. Potential influence of pain-induced bradykinin release on the action of a bradykinin analogue at the blood–brain barrier......... 7. Conclusions ............................................................................................................................................................................ References ..................................................................................................................................................................................

1. Introduction The blood–brain barrier (BBB) serves as a physical and metabolic barrier between the central nervous system (CNS) and the periphery. The BBB is a dynamic structure capable of rapid modulation to maintain homeostasis within the CNS. Decreased BBB function has been described in CNS conditions with pain and / or inflammatory components, including multiple sclerosis [1], Alzheimer’s disease [2], human immunodeficiency virus (HIV) dementia [3], and meningitis [4]. Recent evidence has indicated that peripheral inflammation also alters the structure and increases the permeability of the BBB [5,6]. A potential consequence of increased BBB permeability is altered delivery of therapeutic pharmaceuticals to the CNS. An understanding of how the BBB and its transport / delivery mechanisms are altered during pathological conditions involving pain and / or inflammation is important both in assessing disease etiology and in creating effective therapeutic regimens to treat disease.

2. Function and structure of the blood–brain barrier in health The BBB, located at the level of brain capillary endothelial cells [7], serves to maintain brain homeostasis by regulating the composition of brain extracellular fluid independent of fluctuations within the peripheral circulation. In this manner, the BBB maintains optimal conditions for neuronal function. The structure and function of the BBB have been reviewed [8,9]. Tight junctions (TJs) and the lack of

994 994 995 996 996 996 997 997 997 998 998 998 999

fenestrations at the BBB allow maintenance of CNS homeostasis. TJs in the BBB are composed of transmembrane and cytoplasmic proteins linked to an actin cytoskeleton. TJs impart significant transendothelial electrical resistance (TEER, 1500–2000 V cm 2 ) to brain endothelial cells and severely restrict paracellular diffusion of solutes into the brain [10]. Three integral proteins make up TJs: claudin, occludin, and junction adhesion molecule (JAM). The primary seal of the TJ is formed when claudin dimers bind homotypically to claudins on adjacent endothelial cells [11]. Occludin is a regulatory protein present at TJs, and the presence of occludin is associated with increased TEER and decreased paracellular permeability [12]. JAMs, members of the immunoglobin superfamily, can function in association with platelet endothelial cellular adhesion molecule 1 to regulate leukocyte migration [13]. Cytoplasmic accessory proteins such as zonula occludens proteins (ZO-1, -2, and -3) also play a role in maintaining the function of the BBB. ZO proteins, which belong to the membrane-associated guanylate kinase-like protein family, serve as recognition proteins for TJ placement and as a support structure for signal transduction proteins [14]. Actin, the primary cytoskeletal protein, has known binding sites on all ZO proteins, as well as on claudin and occludin [15]. A dense band of actin and myosin filaments circumscribe endothelial cells, with actin filaments extending into TJs [16]. ZO-1 binds to actin filaments and the C terminus of occludin. Therefore, the structural and dynamic properties of perijunctional actin are coupled to the paracellular barrier. The structural organization of actin has been shown to influence TJ integrity. Actin-disrupting substances have been shown to alter TJ structure and

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

function [17,18], while ATP depletion has been shown to alter TJ structure, decrease TEER, and result in increased association of ZO-1 and -2 with actin [19]. TJs are located at cholesterol-rich regions of the plasma membrane associated with caveolin 1 [20], a molecule which regulates several signal transduction pathways and downstream targets [21]. Several cytoplasmic signaling molecules, including protein kinase C (PKC) and Ca 21 , are located at TJ complexes and are involved in signaling cascades that control TJ assembly and disassembly [22]. PKC serves to regulate TJ formation and function [23]. ZO proteins are thought to serve as scaffolding for PKC signal transduction pathways; in turn, PKC has been shown to play a role in the migration of intracellular ZO-1 to the plasma membrane [24]. PKCj and PKCl and their specific binding protein have been shown to be located at TJs. These proteins have been implicated in the establishment of cell polarity, which is fundamental to BBB differentiation and function [25]. TJ activity is regulated by both intracellular and extracellular Ca 21 . Removal of extracellular Ca 21 has been associated with a decrease in TEER across the membrane and an increase in permeability [18] via heterotrimeric G protein and PKC signaling mechanisms. Homotypic interaction of E-cadherin, which is thought to be the initial event of junctional complex formation, also depends on extracellular Ca 21 [26]. Intracellular Ca 21 regulates cell–cell contact [27], TEER [27], migration of intracellular ZO-1 to the plasma membrane [28], and assembly of TJs [29].

3.1. Diffusion

3. Drug delivery across the blood–brain barrier in health

3.3. Endocytosis

The barrier properties of the BBB result in limited brain penetration of a number of substances. Selective transport mechanisms present at the BBB include diffusion, carrier-mediated transport, and receptor-mediated, adsorptive, and fluid-phase endocytosis [30,31]. BBB efflux transporters that actively transport compounds from the brain to the blood serve to maintain brain homeostasis but also limit the uptake of therapeutic compounds into the CNS [32] (Fig. 1).

989

Diffusion across the BBB is typically transcellular since TJs restrict the paracellular diffusion of solutes [10]. Therefore, the lipophilicity and hydrogen bonding potential of a solute determine its ability to diffuse into the brain; in general, greater lipophilicity and lower hydrogen bonding potential of a compound are associated with greater transcellular diffusivity [33–36].

3.2. Carrier-mediated transport Carrier-mediated transport at the BBB involves a substrate–transporter interaction on the brain endothelial surface. Carrier-mediated transport is a saturable process and is typically classified according to the energy requirements for transport and / or cotransport of another substance (symport or antiport) [31]. Transport of essential compounds, including amino acids, monocarboxylic acids, sugars, and nucleosides, in and / or out of the brain has been shown to occur via specific carrier-mediated transporters. Transporters have been identified at the BBB for sugars such as glucose and mannose; neutral amino acids such as phenylalanine, leucine, and tyrosine; acidic amino acids such as glutamate and aspartate; basic amino acids such as arginine and lysine; b-amino acids such as b-alanine; monocarboxylic acids such as lactate, ketone bodies, and other short-chain fatty acids; amines such as mepyramine; the purine bases adenine and guanine; and peptides such as vasopressin [37,38].

The BBB has reduced endocytosis compared to other tissues [39]; nevertheless, vesicular transport (via receptor-mediated, adsorptive, or fluid-phase endocytosis) plays an important role in the delivery of several compounds to the brain. The iron-bound iron transport protein transferrin has been shown to be endocytosed into the cerebral microvasculature via a receptor-mediated mechanism [40,41]. Similarly, insulin and low-density lipoproteins (LDLs) have been shown to undergo receptor-mediated endocytosis at the BBB [42,43]. Adsorptive endocytosis

990

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

Fig. 1. Transport mechanisms across the blood–brain barrier (BBB). (A) Transcellular diffusion; (B) paracellular diffusion; (C) carrier-mediated transport; (D) fluid-phase endocytosis; (E) adsorptive endocytosis; (F) receptor-mediated endocytosis; and (G) drug efflux.

has been identified as the mechanism of uptake of certain cationized proteins [44] and peptides [45] into the brain. Fluid-phase endocytosis has been demonstrated in vitro in both bovine [46] and human [47] BBB cell culture systems.

3.4. Drug efflux The impact of efflux transporters on drug design and delivery to the CNS has been reviewed [32].

Drugs [48,49], nutrients, metabolites, peptides, hormones, and neurotransmitters [50] can be actively transported from the brain to the blood to maintain brain homeostasis. Active transport out of the brain occurs via efflux transporters localized at the BBB, including P-glycoprotein (P-gp), members of the multidrug resistance-associated protein (MRP) family, monocarboxylic acid transporters, and organic ion transporters [32]. Efflux at the BBB has been shown to limit the penetration of therapeutic compounds such as anti-HIV drugs [51,52], analgesics [53],

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

991

antibacterials [54,55], antiepileptics [56], and anticancer agents [57,58] into the CNS.

adrenal (HPA) axis. These pain mechanisms and their influences on drug delivery across the BBB will be discussed in the following sections (Fig. 2).

4. Pain mechanisms

4.1. Immune and central nervous system responses

Pain is a complex phenomenon involving responses from the immune system and the CNS, as well as activation of the hypothalamic–pituitary–

The immune response is characterized by the rapid production and release of inflammatory mediators such as cytokines, chemokines, cellular adhesion

Fig. 2. Physiological responses to pain and their potential influences on drug delivery at the BBB.

992

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

molecules, matrix metalloproteinases (MMPs), kinins, and prostaglandins (PGs) at the site of disease or injury. Inflammation is typified by increased vascular permeability, localized edema formation, erythema, and increased leukocyte migration. The CNS utilizes neuronal pathways to signal the immune system. The neuronal response to noxious stimulation involves both excitatory and inhibitory neurotransmission within the sensory areas of the spinal cord, and the balance of these CNS responses determines the level of transmission of nociceptive signals to the brain [59]. Furthermore, proinflammatory mediators produced and released in the CNS following local injury or inflammation play a role in the central-mediated pain response.

4.1.1. Cytokines and chemokines Cytokines can either be released in the periphery or the CNS during disease or in response to trauma. Numerous cytokines are involved in the immune response, particularly the interleukins IL-1a and -1b, -2, -4, -6, -8, -10, and -13, tumor necrosis factor-a (TNF-a), and the type I interferons IFN-a and -b [60]. Both excitatory and inhibitory cytokines play a role in inflammation. TNF-a, IL-2, IL-6, IL-8, and IL-1b have been shown to be hyperalgesic [61–65]. Cytokines have also been shown to interact with kinins to potentiate their effects [66]. Changes in expression of endothelial surface molecules (adhesion molecules such as selectins and integrins) and adhesion of polymorphoneutrophils (PMNs), monocytes, and lymphocytes to cell walls have been shown to be induced by proinflammatory cytokines such as IL-1b. Inhibitory cytokines, including IL-4, IL-10, and IL-13, modulate the immune response by exerting anti-inflammatory actions [66] and inhibiting the synthesis of proinflammatory cytokines such as IL-1b and TNF-a [67]. Peripheral cytokines such as IL-1, IL-6, and TNFa have been proposed to activate central responses to peripheral insult. Active transport systems for IL-1 and TNF-a exist at the BBB [68,69]; however, little bioavailable IL-1 or TNF-a circulates from the site of injury or inflammation, except in severe trauma [70]. It has been proposed that IL-1 and TNF-a instead induce IL-6, a cytokine whose circulating levels increase by several orders of magnitude during the development of fever [71]. Peripheral cytokines

may also influence the CNS via neural pathways [72]. While constitutive expression of cytokines in the CNS is low, ‘‘activated’’ microglia, neurons, astroglia, perivascular cells and endothelial cells release cytokines such as IL-1b, IL-6, and TNF-a in response to CNS tissue damage or infection associated with pathological states [70]. Levels of cytokine expression depend on brain region, with the greatest levels in the hypothalamus and hippocampus and lower levels in the cortex and brain stem [73–76]. Chemotactic cytokines, or chemokines, play inflammatory, homeostatic, angiostatic, and / or angiogenic roles in disease [77]. Inflammatory chemokines interact with seven-transmembrane G protein-coupled receptors expressed on leukocytes in order to recruit these molecules to the site of inflammation [78,79]. Chemokines have also been shown to regulate cytokine production [80,81]. Chemokines are expressed in the CNS as well as the periphery. Chemokines such as monocyte chemotactic proteins (MCPs), macrophage inflammatory protein 1-a and -b, regulated on activation normal T-cell expressed and secreted, and interferon-inducible protein 10 are produced in astrocytes, microglia, and perivascular leukocytes during inflammatory diseases such as multiple sclerosis and following brain injury [82].

4.1.2. Cellular adhesion molecules Increased leukocyte migration is a hallmark of the immune response. Receptors on the surface of leukocytes are classified either as selectins or integrins. While selectins take part in initial interactions of leukocytes with cell surfaces, integrins participate in adhesion and transmigration processes [83,84]. Endothelial cell ‘‘activation’’ following an immune challenge results in upregulation of the expression of genes that encode for leukocyte adhesion receptors [85,86] such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [85–87]. Interactions between endothelial cell receptors and selectins and integrins result in leukocyte adhesion to and migration across endothelial cells of the BBB. Leukocyte trafficking involves rolling, tethering, firm adhesion, diapedesis, and chemotaxis of leukocytes [88]. Following ‘‘activation’’ of the endo-

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

thelium by inflammatory mediators, leukocytes reversibly adhere to the endothelium. Under conditions of flow, this initial adhesion results in rolling of leukocytes. The interaction between selectins and cell membrane glycoproteins tether leukocytes to the endothelium. Integrin receptors on tethered leukocytes are then ‘‘activated’’ by inflammatory mediators such as endothelial membrane-expressed platelet-activating factor or chemokines. Firm adhesion of leukocytes to the endothelium becomes possible since ‘‘activated’’ integrin receptors possess greater affinity for the endothelium. Adherent migrating leukocytes move over the endothelium and diapedese between endothelial cells to enter extravascular tissue. During diapedesis, leukocytes have been shown to signal endothelial cells, disrupting intercellular junction integrity [89]. Leukocytes then transmigrate to the site of immune reaction. The b1 class of integrins, which are the primary integrins expressed on endothelial cells in the CNS [90], play a critical role in regulating BBB function. A number of other integrins are expressed in the CNS, including av integrins, which are expressed on neurons, glial cells, meningeal cells, and endothelial cells [91,92], and b2 integrins, which are expressed on microglia and infiltrating leukocytes [91,93]. Integrins appear to play a role during CNS inflammation, since their expression has been shown to be altered during inflammatory diseases such as multiple sclerosis [94]. Furthermore, TNF-a, IL1-b, and IFN-g, cytokines that are elevated in inflammatory CNS disease, have been shown to induce expression of the adhesion molecules ICAM-1 and VCAM-1 on brain endothelial cells and astrocytes [95].

4.1.3. Matrix metalloproteinases Vascular endopeptidases known as MMPs play a role in vascular remodeling following inflammation, injury, and / or oxidative stress. MMP activity in the vasculature is rigorously controlled by tissue inhibitors of metalloproteinases (TIMPs). Stresses upregulate MMP expression and activity, disrupting the balance of MMPs and TIMPs. This imbalance then leads to extracellular matrix reorganization and degradation [96]. MMP release from inflammatory cells occurs following stress. MMPs are normally present in the brain in latent forms. ‘‘Activated’’ MMPs, which are

993

secreted by microglia, astrocytes, and endothelial cells in the CNS in response to trauma or disease, contribute to tissue damage [97] and opening of the BBB [98,99]. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) have been shown to degrade the major components of the basal lamina of cerebral blood vessels [100]. Furthermore, TNF-a, a cytokine which induces BBB opening, has been linked to MMP-9 (gelatinase B) expression [97]. In addition, cytokines secreted from ‘‘activated’’ macrophages upregulate MMP gene expression in the vasculature [101,102].

4.1.4. Kinins Kinins act on seven-transmembrane G proteincoupled B 1 or B 2 receptors to activate and sensitize nociceptors [103–105]. Bradykinin (BK) is well characterized [106–109] and has been shown to interact with B 2 receptors. The action of BK involves activation of phospholipase C followed by stimulation of PKC and an increase in Na 1 conductance. The result of these modulations is depolarization of sensory afferent neurons and hyperalgesia [110,111]. Kinins not only activate and sensitize nociceptors, but also exert proinflammatory effects, resulting in vasodilation, edema, and the release of other inflammatory molecules [66]. Mechanisms for the synthesis of kinins are present in the CNS [112]. Furthermore, kinins and their receptors have been detected in the brain in vivo and in vitro [113–115]. B 2 receptors have been identified on CNS microglia, the primary immune effector cell population in the CNS, as well as on endothelial cells [116,117]. The mechanism of BK in the cerebral vasculature is thought to be similar to its action in the periphery. BK stimulates neural and neuroglial cells, resulting in production and release of PG precursors, cytokines, free radicals, and nitric oxide. These actions of BK result in damage to neural cells and disturbance of BBB function [112]. Furthermore, activation of CNS astrocytes by kinins has been linked to glutamate release and increases in neuronal Ca 21 [118]. 4.1.5. Prostaglandins PGs play a critical role in the modulation of immune function [119,120]. Inflammatory insult leads to the release of arachidonic acid (AA) from membrane phospholipids via phospholipase A 2 ac-

994

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

tion. The cyclooxygenase enzymes COX-1 and COX-2 convert AA to prostaglandin H 2 , which is then converted into different PGs, including PGI 2 , PGF 2a , PGD 2 and PGE 2 . Inflammation involves primarily PGE 2 and PGI 2 [121]. PGE 2 is one of the best-characterized PGs; it is secreted by fibroblasts, macrophages, and malignant cells following an immune challenge, resulting in vasodilation and subsequent erythema and edema formation [122]. Furthermore, PGE 2 controls the production of cytokines by ‘‘activated’’ macrophages [123,124] and induces the synthesis of MMPs [122], leading to reorganization and degradation of the extracellular matrix. Stimulation of CNS cells by inflammatory cytokines such as IL-1b and TNF-a results in production and release of PGE 2 by almost all CNS cell types, including brain endothelial cells [125–130]. The COX-2 enzyme, which plays a role in PG synthesis, has been shown to be upregulated in the excitatory neurons of the cerebral cortex and hippocampus following insult related to overstimulation of Nmethyl-D-aspartate (NMDA) receptors [131–133]. Furthermore, TNF-a has been shown to induce COX-2 expression in brain microvessel endothelial cells [128]. PGE 2 has been shown to induce the IL-6-type cytokine oncostatin-M in microglia [134], resulting in astrocytic production of IL-6 [135] and upregulation of ICAM-1, IL-6, and the chemokine MCP1 in human cerebral endothelial cells [136].

4.1.6. Excitatory peptides and amino acids Excitatory peptides in the CNS also play a role in nociception. The peptides present in the greatest abundance within the dorsal horn are substance P (SP) and calcitonin gene-regulated peptide (CGRP). SP, a member of the tachykinin family, acts on neurokinin NK 1 receptors causing long-lasting depolarization via inactivation of K 1 and / or activation of Na 1 or Ca 21 currents [137]. Synaptic depolarization and the increase in Ca 21 in turn induce the protooncogene c-fos, resulting in production of c-fos protein, a neural marker of pain [138]. Furthermore, SP stimulates the release of the proinflammatory mediator histamine from mast cells [139], increasing microvascular permeability at the BBB. CGRP enhances the action of SP by altering its breakdown by competing for the same degradatory enzyme [140]. The majority of excitatory neurotransmission with-

in the CNS is associated with activation of a-amino3-hydroxy-5-methyl-isoxazole-4-propionic acid and NMDA receptors on spinal neurons by glutamate (Glu) [141–144], an excitatory amino acid present in large sensory fibers and nociceptive neurons [59]. While Glu receptors have been shown to be present on astrocytes [145], conflicting evidence exists as to whether these receptors are expressed on cerebral endothelial cells [146–149]. NMDA receptor activation results in production of nitric oxide (NO) and adenosine. NO can diffuse to afferent terminals to activate guanylate cyclase, resulting in stimulation of cGMP and a further release of Glu [59].

4.2. Activation of the hypothalamic–pituitary– adrenal axis The CNS regulates the immune system primarily via activation of the HPA axis. Stress responses due to physical, emotional, and environmental stimuli result in activation of the HPA axis and initiation of a ‘‘stress cascade’’ [150]. Cytokines have been shown to activate the HPA axis at the level of the CNS. The effects of cytokine administration on plasma levels of adrenocorticotropin (ACTH), corticosterone, and other mediators of the HPA axis have been reviewed [151]. Upon activation of the HPA axis, corticotropin-releasing hormone (CRH) is released from the hypothalamus, and circulating CRH and vasopressin stimulate the expression and release of ACTH from the anterior pituitary. ACTH circulates to the adrenal glands, where it induces the production and release of glucocorticoids, stress hormones that are responsible for downregulation of the immune response [150]. Glucocorticoids modulate the expression of cytokines and adhesion molecules and regulate immune cell trafficking, expression, and differentiation, as well as expression of chemoattractants, chemotaxis, and production of inflammatory mediators. Furthermore, glucocorticoids negatively feed back to inhibit the release of CRH [152,153].

5. Alterations of the blood–brain barrier by pain mediators Pain mediators involved in CNS disease and injury have been shown to alter the structure and function

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

of the BBB. Additionally, peripheral inflammatory pain has been shown to alter the cytoarchitecture and permeability of the BBB [5,6]. Perturbations of tight and adherens junctions have been shown to play a role in the pathogenesis of many diseases [9]. Inflammatory permeability is thought to occur following a loss of interendothelial junction integrity during which cell–cell borders actively contract and passively recoil, resulting in larger endothelial clefts [154–157]. A potential consequence of increased BBB permeability is altered transport of therapeutic compounds to the CNS.

5.1. Effects of proinflammatory mediators on the blood–brain barrier Cytokines appear to play a key role in BBB disruption in models of CNS inflammation and injury. Exposure of cultured rat cerebral endothelial cells to TNF-a, IL-1b, and IL-6 has been shown to result in decreased TEER; this decrease has been shown to be countered by administration of indomethacin, a COX inhibitor [158]. Furthermore, TNF-a has been shown to induce COX-2 expression and prostaglandin release in brain microvessel endothelial cells [128]. Therefore, it has been proposed that cyclooxygenase activation within endothelial cells plays a role in BBB disruption. Furthermore, endothelial permeability has been shown to be increased in vitro by IL-1a via a decrease in plasma membrane-associated tyrosine phosphatase activity [159]. Such a decrease has been associated with decreased tyrosine phosphorylation of tight junction proteins, disintegration of adherens junctions, and decreased TEER [160–162]. Intrastriatal injection of IL-1b in rats has been associated with a neutrophildependent increase in BBB permeability [163,164]. The mechanism of this permeability increase has been attributed to loss of the tight junction proteins occludin and ZO-1 and redistribution of the adherens junction protein vinculin [163]. TNF-a, on the other hand, has been shown to downregulate the tight junction protein occludin in astrocytes (which do not form a permeability barrier) but not cerebral endothelial cells [165]. In addition, TNF-a has been shown to alter receptor-mediated endocytosis of LDLs and the iron-binding protein transferrin (TF) at the BBB [166]. Chemokines, which are produced and released

995

following inflammatory insult, recruit leukocytes to the site of inflammation. Adhesion of leukocytes to the endothelium and recruitment of these cells into the CNS, in turn, have been shown to modulate BBB permeability in a number of CNS disorders. ICAM-1 on endothelial cells and its integrin receptor on circulating leukocytes are necessary for tethering of leukocytes to the BBB [95]. The loss of the tight junction proteins occludin and ZO-1 and redistribution of vinculin have been shown to be accompanied by increased expression of ICAM-1 by endothelial cells, adhesion of PMNs by an integrin-dependent interaction [167], and increased flux of PMNs across the BBB [163]. Furthermore, increased phosphotyrosine staining has been shown in areas with extensive PMN recruitment, indicating that migrating PMNs initiate a signaling cascade that results in TJ protein phosphorylation, modulation of BBB permeability, and reorganization of adherens junctions [167]. The presence of perivascular macrophages has been shown to facilitate infiltration of more monocytes via alterations of TJ proteins and thereby enhance disease progression in a model of HIV-1associated dementia [168]. ‘‘Activated’’ MMPs produced by microglia, astrocytes, and endothelial cells in the CNS contribute to tissue damage [97] and opening of the BBB [98,99]. MMP-associated changes in microvascular permeability have generally been attributed to the effects of these enzymes on the extracellular matrix [169]. However, occludin has recently been shown to be a non-matrix target of MMPs [170]. MMP-2 is expressed constitutively in endothelial cells and is known to be distributed near interendothelial junctions, spatially close to occludin, making this TJ protein a potential target of MMP-2. Furthermore, inflammatory mediators have been shown to alter the distribution of MMP-2. It has been proposed that degradation of TJ proteins by MMPs could increase endothelial permeability for a prolonged period; only following synthesis of new proteins could TJ integrity be recovered. Since MMP-9 is expressed weakly by endothelial cells in the absence of cytokines, MMP-linked, protein synthesis-independent changes in endothelial permeability have been attributed to activation of the constitutive MMP-2 [171]. BK-mediated increases in BBB permeability have been shown to be blocked by a combination of indomethacin (a COX inhibitor) and nor-

996

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

dihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and by superoxide dismutase and catalase (free radical scavengers). Therefore, it has been proposed that BK increases BBB permeability via a B 2 receptor-mediated mechanism involving activation of phospholipase A 2 , release of arachadonic acid, and production of free radicals [172]. Furthermore, the BK analogue RMP-7 has been shown to open the BBB to lanthanum in vivo by altering the integrity of endothelial tight junctions [173]. IFN-g treatment has been shown to produce upregulation of B 1 receptors on human brain endothelial cells; application of a B 1 agonist was shown to stimulate NO production, increase BBB permeability, and inhibit IL-8 release in vitro [174].

5.2. Effects of excitatory peptides and amino acids on the blood–brain barrier It has been proposed that SP possesses an immunomodulatory action at the BBB during inflammation and autoimmune disease. SP secretion has been observed in rat brain endothelial cells following stimulation by the proinflammatory cytokines IL-1b and TNF-a. Further, a portion of this SP has been found to bind to brain endothelial cells [175]. SP has been shown to stimulate translocation of PKC in bovine cerebral microvessels, indicating that this peptide may play a role in the regulation of BBB protein phosphorylation [176]. Additionally, receptors for CGRP, a peptide which has been shown to enhance the actions of SP by slowing its degradation [140], have been identified in human brain astrocytes and cerebromicrovascular endothelial cells [177], suggesting a possible role of this peptide in regulation of the BBB. Brain Glu concentrations in the intracellular space are higher than those in the extracellular space under normal conditions [178–180]. However, brain injury and disease have been shown to increase levels of extracellular Glu [178–183]. Glu has been shown to induce the synthesis of inflammatory mediators such as brain platelet-activating factor and NO in vivo [180,184]. Further, it has been proposed that disruption of the BBB may result from indirect actions of Glu, including induction of apoptosis in perivascular glia [183] or stimulation of NO production [180,184]. NO has been implicated in increased BBB permeability following application of Glu to cerebral

endothelial cells in vitro [180]. Additionally, leukocyte recruitment has been observed parallel to BBB breakdown following intracerebrally injected NMDA in adult and juvenile rats [185]. ‘‘Activated’’ PMNs have been shown to release Glu and upregulate expression of Glu receptors, resulting in decreased BBB function [148].

5.3. Effects of hypothalamic–pituitary–adrenal axis activation on the blood–brain barrier Emotional stress has been shown to precipitate or worsen several neuroinflammatory disorders [186] including relapsing-remitting multiple sclerosis [187–189]. Stress responses activate the HPA axis through release of CRH from the hypothalamus, resulting in production of glucocorticoids to downregulate the immune response [150]. It has been hypothesized that CRH released in acute stress either affects the BBB directly or via mast cell activation. Mast cells are found throughout the periphery and CNS and play a critical role in the development of allergic reactions [190]. Mast cells are thought to modulate BBB permeability since many mast cell mediators, including TNF-a and histamine, are vasoactive [191]. In fact, recent studies have shown that CRH has proinflammatory effects which are mediated via mast cell activation [192,193]. Furthermore, acute, non-traumatic stress has been shown to increase BBB permeability and activate mast cells [194], supporting the hypothesis that mast cell activation in response to stress influences BBB permeability.

6. Implications of pain responses in central nervous system drug delivery Painful and / or inflammatory conditions can be treated with a number of different classes of drugs, including anti-HIV drugs, antibiotics, opioid analgesics, antineoplastics, and antiepileptics. Pain and inflammatory mediators and their analogues have been shown to alter the function of the BBB. One consequence of BBB disruption has been shown to be increased drug delivery to the brain. This altered delivery may be detrimental in the case of drugs with narrow therapeutic ranges. On the other hand, in-

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

creased delivery to the brain may be beneficial for targeting disorders within the CNS.

6.1. Influence of increased blood–brain barrier paracellular permeability on drug delivery to the brain The TJs of the BBB prevent passage of small, hydrophilic molecules from the blood to the brain. During pain or inflammation, however, TJ structure has been shown to be modified, resulting in increased BBB permeability. Increased delivery of drugs, a potential consequence of this increased permeability, may be beneficial or detrimental. Few studies have been performed concerning the relationship among pain mediators, BBB paracellular permeability, and drug delivery. Several key studies involve transport of the platinum chemotherapeutic agent cisplatin (CIS) across the BBB. Lipopolysaccharide (LPS) has been shown to decrease TEER in bovine cerebral endothelial cells, indicating an ‘‘opening’’ of intercellular tight junctions [195]. Under normal conditions, CIS does not readily cross the BBB due to its hydrophilicity [196]. However, LPS administration and subsequent production of inflammatory mediators have been shown to enhance platinum content in the cerebral cortex [197]. The disabling neurotoxicity that has been observed following CIS readministration [198] has therefore been attributed to increased transport of the drug across a compromised BBB [197], likely via paracellular diffusion. TNF-a, which has also been shown to decrease TEER in vitro [158], has been shown to increase CIS transport across bovine brain microvessel endothelial cells [199], providing further evidence that BBB disruption by inflammatory mediators plays a role in CIS delivery to the brain. In this study, it was proposed that combined administration of TNF-a and CIS could be clinically useful in patients with CNS tumors.

6.2. Influence of altered blood–brain barrier endocytosis on drug delivery to the brain The BBB restricts the entry of most proteins and large-molecular weight molecules into the brain. However, receptors on the surface of brain capillary endothelial cells play an important role in selective transport of substances such as TF (an iron-binding

997

protein), insulin, and LDLs across the BBB via receptor-mediated endocytosis [40–43]. The TF receptor and its substrate have in fact been exploited for delivery of therapeutic agents to the CNS. Biotinylated basic fibroblast growth factor and brainderived neurotrophic factor, potent neuroprotective agents, have been delivered across the BBB via incorporation into a peptide drug delivery vector containing murine OX26, a monoclonal antibody against the rat TF receptor which undergoes receptor-mediated transport [200–202]. This delivery vector has also been utilized for delivery of antiAlzheimer’s and anti-HIV antisense molecules across the BBB [203]. TF itself has been utilized to carry therapeutic agents across the BBB; conjugation of nerve growth factor to TF via avidin / biotin technology has been shown to be as effective in transporting biotinylated therapeutics as OX26 [204]. Alterations in receptor-mediated endocytosis during neuropathological conditions could potentially influence the delivery of compounds such as insulin, therapeutic drug delivery vectors, or transferrinconjugated drugs across the BBB. It has been shown that the process of receptor-mediated endocytosis is altered during neuropathological conditions. Neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease have been associated with increased levels of iron and oxidative stress in the brain [205–207]. It has been proposed that one of the causes of neuronal death in such diseases involves disruption in iron transport protein expression [208,209]. Inflammatory mediators have also been shown to influence receptor-mediated endocytosis in vitro. TNF-a has been shown to alter receptor-mediated endocytosis and transendothelial transport of LDLs and TF. These modifications, significant since both iron and lipids are essential for normal growth and function of brain cells, were proposed to be due to a change in intracellular traffic kinetics, since no increase in LDL or TF receptor expression was observed at the BBB [166].

6.3. Potential influence of altered blood–brain barrier efflux on drug delivery to the brain Membrane efflux pumps at the BBB, including P-gp, organic anion transporters, and MRP, limit penetration of drugs into the CNS by actively transporting them out of the brain. Drug efflux has

998

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

been linked to multidrug resistance, which has been described as an acquired or intrinsic resistance to therapy, in a number of pathologies. Efflux transporter function at the BBB has been associated with minimal effectiveness of anti-HIV drugs on AIDS dementia, antibacterials on CNS infection, opioids on CNS-based pain, and chemotherapy on brain tumors [32]. BBB efflux of a number of drugs has been shown to be influenced by putative specific inhibitors of efflux transporters [210–213]. Increased multidrug resistance (MDR1) gene mRNA and P-gp protein expression have been observed in brain specimens taken from patients with medically intractable epilepsy [214]. Furthermore, increased efflux transporter expression has been observed in cultured rat brain endothelial cells subjected to the oxidative stress of ischemia / reperfusion [215]. The possibility of alterations in the expression and function of efflux transport proteins and the MDR1 gene at the BBB during pain or inflammation remains to be investigated. However, such alterations have been observed in other cell lines following stimulation with proinflammatory mediators [216–218].

6.4. Potential influence of pain-induced glutamate release on the delivery of glutamate-conjugated drugs to the brain Glutamate (Glu), a neurotransmitter present in large sensory fibers and nociceptive neurons [59], initiates excitatory neurotransmission in the CNS via activation of NMDA receptors [141–144]. ‘‘Activated’’ PMNs have been shown to release Glu and upregulate expression of Glu receptors, resulting in decreased BBB function [148]. Conjugation of the BBB-impermeable drug p-di(hydroxyethyl)-aminoD-phenylalanine (an analogue of the antitumor agent D-melphalan) to L-Glu has resulted in improved permeability of the drug in vitro and in vivo via the L-Glu transport system. 5,7-Dichlorokynurenic acid and its conjugates ( L-Glu, L-Asp, and L-Gln), on the other hand, have exhibited a low brain-to-plasma concentration ratio in vivo. Therefore, it has been suggested that facilitation of the delivery of nonpermeable conjugates across the BBB depends on their physicochemical and receptor-binding properties [219,220]. Alterations in delivery of L-Glu conjugates in a cancer model have not been investi-

gated and may be influenced by the release of endogenous Glu and / or alterations in L-Glu transporter expression or activity in response to cancerrelated pain. The presence of endogenous Glu may effectively reduce the dose of Glu-conjugated drug to reach the brain. Furthermore, possible pain-induced alterations in Glu transporter expression or activity could influence the dose of Glu-conjugated drug required to elicit a therapeutic effect.

6.5. Potential influence of pain-induced bradykinin release on the action of a bradykinin analogue at the blood–brain barrier An analogue of the inflammatory mediator BK has been designed to transiently increase the permeability of the BBB and the blood–brain tumor barrier (BBTB). Labradimil (LAB) (also known as Cereport or RMP-7) is a nine-amino-acid peptide which selectively binds to the bradykinin B 2 receptor. In vitro, LAB initiates BK-like second messenger cascades, including increases in intracellular Ca 21 and turnover of phosphatidylinositol. The mechanism of intravenous LAB has been shown to involve disengagement of the TJs of endothelial cells that make up the BBB [221]. Pharmacological opening of the BBB and BBTB via LAB administration has been shown to be clinically relevant in the treatment of gliomas using antineoplastic agents such as carboplatin [221– 224]. Alterations in delivery of LAB during cancer have not been investigated and may be influenced by the release of endogenous BK and / or alterations in B 2 receptor expression or activity due to cancerrelated pain. The presence of endogenous BK may effectively reduce the dose of LAB needed to transiently open BBB TJs; furthermore, possible pain-induced alterations in B 2 receptor expression or activity could influence the required dose of LAB.

7. Conclusions The BBB plays a critical role in maintaining cerebral homeostasis by separating the CNS from the periphery. In health, the BBB serves to control the passage of solutes into and out of the brain. During pathological insult, the BBB is capable of rapid

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

modulation; in all but the most extreme cases, the BBB is able to ‘‘bend without breaking’’, or yield increased permeability while maintaining structural integrity. The structure and function of the BBB has been shown to be altered in a number of diseases with pain and / or inflammatory components. Evidence has shown that a number of mediators involved in the pain response, including cytokines, chemokines, cellular adhesion molecules, MMPs, kinins, PGs, excitatory molecules such as SP and Glu, and CRH, play roles in altering the cytoarchitecture and permeability of the BBB. Inflammatory mediators have also been shown to alter receptor-mediated endocytotic uptake at the BBB. Furthermore, the release of endogenous inflammatory mediators during pain could potentially influence the uptake of drugs meant to utilize specific transporters or activate receptors at the BBB. While little is known about the effects of pain mediators on efflux transporter expression and activity at the BBB, such alterations have been observed in epilepsy; efflux has been shown to be altered in other cell lines in response to proinflammatory mediators as well. Therefore, an understanding of alterations in drug efflux at the BBB during pain and / or inflammation may be of significant importance in predicting therapeutic outcomes. Increased drug delivery to the brain is a potential consequence of pain- and / or inflammation-induced BBB disruption. This altered delivery may be either detrimental (resulting in CNS toxicity) or beneficial (resulting in improved therapeutic outcome) based on the drug and its intended site of action. An understanding of BBB structural, functional, and transport alterations in pain and / or inflammation will result in new and more effective therapeutic approaches to treating disease.

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

References [16] [1] M. Trojano, C. Manzari, P. Livrea, Blood–brain barrier changes in multiple sclerosis, Ital. J. Neurol. Sci. 13 (1992) 55–64. [2] R.N. Kalaria, Cerebral vessels in ageing and Alzheimer’s disease, Pharmacol. Ther. 72 (1996) 193–214. [3] L.M. Dallasta, L.A. Pisarov, J.E. Esplen, J.V. Werley, A.V. Moses, J.A. Nelson, C.L. Achim, Blood–brain barrier tight

[17]

[18]

999

junction disruption in human immunodeficiency virus-1 encephalitis, Am. J. Pathol. 155 (1999) 1915–1927. K.S. Kim, C.A. Wass, A.S. Cross, Blood–brain barrier permeability during the development of experimental bacterial meningitis in the rat, Exp. Neurol. 145 (1997) 253–257. J.D. Huber, K.A. Witt, S. Hom, R.D. Egleton, K.S. Mark, T.P. Davis, Inflammatory pain alters blood–brain barrier permeability and tight junctional protein expression, Am. J. Physiol. Heart Circ. Physiol. 280 (2001) H1241–H1248. J.D. Huber, V.S. Hau, L. Borg, C.R. Campos, R.D. Egleton, T.P. Davis, Blood–brain barrier tight junctions are altered during a 72-h exposure to lambda-carrageenan-induced inflammatory pain, Am. J. Physiol. Heart Circ. Physiol. 283 (2002) H1531–H1537. T.S. Reese, M.J. Karnovsky, Fine structural localization of a blood–brain barrier to exogenous peroxidase, J. Cell Biol. 34 (1967) 207–217. L.R. Drewes, Molecular architecture of the brain microvasculature: perspective on blood–brain transport, J. Mol. Neurosci. 16 (2001) 93–98. J.D. Huber, R.D. Egleton, T.P. Davis, Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier, Trends Neurosci. 24 (2001) 719–725. A.M. Butt, H.C. Jones, N.J. Abbott, Electrical resistance across the blood–brain barrier in anaesthetized rats: a developmental study, J. Physiol. 429 (1990) 47–62. M. Furuse, H. Sasaki, S. Tsukita, Manner of interaction of heterogeneous claudin species within and between tight junction strands, J. Cell Biol. 147 (1999) 891–903. T. Hirase, J.M. Staddon, M. Saitou, Y. Ando-Akatsuka, M. Itoh, M. Furuse, K. Fujimoto, S. Tsukita, L.L. Rubin, Occludin as a possible determinant of tight junction permeability in endothelial cells, J. Cell Sci. 110 (1997) 1603– 1613. I. Martin-Padura, S. Lostaglio, M. Schneemann, L. Williams, M. Romano, P. Fruscella, C. Panzeri, A. Stoppacciano, L. Ruco, A. Villa, D. Simmons, E. Dejana, Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration, J. Cell Biol. 142 (1998) 117–127. J. Haskins, L. Gu, E.S. Wittchen, J. Hibbard, B.R. Stevenson, ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin, J. Cell Biol. 141 (1998) 199–208. M. Itoh, M. Furuse, K. Morita, K. Kubota, M. Saitou, S. Tsukita, Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH terminii of claudins, J. Cell Biol. 147 (1999) 1351–1363. N. Hirokawa, L.G. Tilney, Interactions between actin filaments and between actin filaments and membranes in quickfrozen and deeply etched hair cells of the chick ear, J. Cell Biol. 95 (1982) 249–261. C.J. Bentzel, B. Hainau, A. Edelman, T. Anagnostopoulos, E.L. Benedetti, Effect of plant cytokinins on microfilaments and tight junction permeability, Nature 264 (1976) 666–668. B.R. Stevenson, D.A. Begg, Concentration-dependent effects

1000

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26] [27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006 of cytochalasin D on tight junctions and actin filaments in MDCK epithelial cells, J. Cell Sci. 107 (1994) 367–375. T. Tsukamoto, S.K. Nigam, Tight junction proteins form large complexes and associate with the cytoskeleton in an ATP depletion model for reversible junction assembly, J. Biol. Chem. 272 (1997) 16133–16139. A. Nusrat, C.A. Parkos, P. Verkade, C.S. Foley, T.W. Liang, W. Innis-Whitehouse, K.K. Eastburn, J.L. Madara, Tight junctions are membrane microdomains, J. Cell Sci. 113 (2000) 1771–1781. A. Schlegel, M.P. Lisanti, The caveolin triad: caveolae biogenesis, cholesterol trafficking, and signal transduction, Cytokine Growth Factor Rev. 12 (2001) 41–51. J.L. Madara, C. Parkos, S. Colgan, A. Nusrat, K. Atisook, P. Kaoutzani, The movement of solutes and cells across tight junctions, Ann. N. Y. Acad. Sci. 664 (1992) 47–60. R.O. Stuart, S.K. Nigam, Regulated assembly of tight junctions by protein kinase C, Proc. Natl. Acad. Sci. USA 92 (1995) 6072–6076. E. Willott, M.S. Balda, A.S. Fanning, B. Jameson, C. Van Itallie, J.M. Anderson, The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions, Proc. Natl. Acad. Sci. USA 90 (1993) 7834–7838. Y. Izumi, T. Hirose, Y. Tamai, S. Hirai, Y. Nagashima, T. Fujimoto, Y. Tabuse, K.J. Kemphues, S. Ohno, An atypical PKC directly associates and colocalizes at the epithelial tight junction with ASIP, a mammalian homologue of Caenorhabditis elegans polarity protein PAR-3, J. Cell Biol. 143 (1998) 95–106. B.M. Gumbiner, Cell adhesion: the molecular basis of tissue architecture and morphogenesis, Cell 84 (1996) 345–357. S.K. Nigam, E. Rodriguez-Boulan, R.B. Silver, Changes in intracellular calcium during the development of epithelial polarity and junctions, Proc. Natl. Acad. Sci. USA 89 (1992) 6162–6166. R.O. Stuart, A. Sun, M. Panichas, S.C. Hebert, B.M. Brenner, S.K. Nigam, Critical role for intracellular calcium in tight junction biogenesis, J. Cell. Physiol. 159 (1994) 423–433. R.O. Stuart, A. Sun, K.T. Bush, S.K. Nigam, Dependence of epithelial intercellular junction biogenesis on thapsigarginsensitive intracellular calcium stores, J. Biol. Chem. 271 (1996) 13636–13641. N.J. Abbott, I.A. Romero, Transporting therapeutics across the blood–brain barrier, Mol. Med. Today 2 (1996) 106– 113. R.D. Egleton, T.P. Davis, Bioavailability and transport of peptides and peptide drugs into the brain, Peptides 18 (1997) 1431–1439. E.M. Taylor, The impact of efflux transporters in the brain on the development of drugs for CNS disorders, Clin. Pharmakokinet. 41 (2002) 81–92. J.M. Diamond, E.M. Wright, Molecular forces governing non-electrolyte permeation through cell membranes, Proc. Royal Soc. 172 (1969) 273–316. W.M. Pardridge, L.J. Mietus, Transport of steroid hormones

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

through the rat blood–brain barrier. Primary role of albumin bound hormone, J. Clin. Invest. 64 (1979) 145–154. S.J. Weber, D.L. Greene, S.D. Sharma, H.I. Yamamura, T.H. Kramer, T.F. Burks, V.J. Hruby, L.B. Hersh, T.P. Davis, Distribution and analgesia of [ 3 H][D-Pen 2 ,D-Pen 5 ]enkephalin and two halogenated analogs after intravenous administration, J. Pharm. Exp. Ther. 259 (1991) 1109–1117. S.J. Weber, T.J. Abbruscato, E.A. Brownson, A.W. Lipkowski, P. Polt, A. Misicka, R.C. Haaseth, H. Bartosz, V.J. Hruby, T.P. Davis, Assessment of an in vitro blood–brain barrier model using several [Met5] enkephalin opioid analogs, J. Pharm. Exp. Ther. 266 (1993) 1649–1655. A. Tsuji, I. Tamai, Carrier-mediated or specialized transport of drugs across the blood–brain barrier, Adv. Drug Deliv. Rev. 36 (1999) 277–290. I. Tamai, A. Tsuji, Transporter-mediated permeation of drugs across the blood–brain barrier, J. Pharm. Sci. 89 (2000) 1371–1384. M.W. Brightman, T.S. Reese, Junctions between intimately apposed cell membranes in the vertebrate brain, J. Cell Biol. 40 (1969) 648–677. J.B. Fishman, J.B. Rubin, J.V. Handrahan, J.R. Connor, R.E. Fine, Receptor-mediated transcytosis of transferrin across the blood–brain barrier, J. Neurosci. Res. 18 (1987) 299–304. L. Descamps, M.P. Dehouck, G. Torpier, R. Cecchelli, Receptor-mediated transcytosis of transferrin through blood– brain barrier endothelial cells, Am. J. Physiol. 270 (1996) H1149–H1158. G.L. King, S.M. Johnson, Receptor-mediated transport of insulin across endothelial cells, Science (Washington, DC) 227 (1985) 1583–1586. B. Dehouck, M.P. Dehouck, J.C. Fruchart, R. Cecchelli, Upregulation of the low density lipoprotein receptor at the blood–brain barrier: intercommunications between brain capillary endothelial cells and astrocytes, J. Cell Biol. 126 (1994) 465–473. A.K. Kumagi, J.B. Eisenberg, W.M. Pardridge, Adsorptivemediated endocytosis of cationized albumin and a betaendorphin-cationized albumin chimeric peptide by isolated brain microvessel, J. Biol. Chem. 262 (1987) 15214–15219. I. Tamai, Y. Sai, H. Koayashi, M. Kamata, T. Wakamiya, A. Tsuji, Structure-internalization relationship for adsorptivemediated endocytosis of basic peptides at the blood–brain barrier, J. Pharm. Exp. Ther. 280 (1997) 410–415. F.L. Guillot, K.L. Audus, T. Raub, Fluid-phase endocytosis by primary cultures of bovine brain microvessel endothelial cell monolayers, Microvasc. Res. 39 (1990) 1–14. D. Stanimirovic, P. Morley, R. Ball, E. Hamel, G. Mealing, J.P. Durkin, Angiotensin II-induced fluid phase endocytosis in human cerebromicrovascular endothelial cells is regulated by the inositol-phosphate signaling pathway, J. Cell. Physiol. 169 (1996) 455–467. J. Bart, H.J. Groen, N.H. Hendrikse, W.T. van der Graaf, W. Vaalburg, E.G. de Vries, The blood–brain barrier and oncology: new insights into function and modulation, Cancer Treat. Rev. 26 (2000) 449–462. H. Potschka, M. Fedrowitz, W. Loscher, P-Glycoprotein-

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

mediated efflux of penobarbital, lamotrigine, and felbamate at the blood–brain barrier: evidence from microdialysis experiments in rats, Neurosci. Lett. 327 (2002) 173–176. W.A. Banks, Physiology and pathology of the blood–brain barrier: implication for microbial pathogenesis, drug delivery and neurodegenerative disorders, J. Neurovirol. 5 (1999) 538–555. M.A. Hedaya, R.J. Sawchuk, Effect of probenecid on the renal and nonrenal clearances of zidovudine and its distribution into cerebrospinal fluid in the rabbit, J. Pharm. Sci. 78 (1989) 716–722. Y. Wang, R.J. Sawchuk, Zidovudine transport in the rabbit brain during intravenous and intracerebroventricular infusion, J. Pharm. Sci. 84 (1995) 871–876. A.H. Schinkel, E. Wagenaar, L. van Deemter, C.A. Mol, P. Borst, Absence of the mdr1a p-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporine, J. Clin. Invest. 96 (1995) 1698– 1705. H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, M. Hanano, R. Spector, Transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system, J. Pharmacol. Exp. Ther. 250 (1989) 979–984. T. Ooie, T. Terasaki, H. Suzuki, Y. Sugiyama, Kinetic evidence for active efflux transport across the blood–brain barrier of quinolone antibiotics, J. Pharmacol. Exp. Ther. 283 (1997) 293–304. K.D.K. Adkison, A.A. Artru, K.M. Powers, D.D. Shen, Contribution of probenecid-sensitive anion transport processes at the brain capillary endothelium and choroids plexus to the efficient efflux of valproic acid from the central nervous system, J. Pharmacol. Exp. Ther. 268 (1994) 797– 805. A.H. Schinkel, J.J.M. Smit, O. van Tellingen, J.H. Beijnen, E. Wagenaar, L. van Deemter, C.A. Mol, M.A. van der Valk, E.C. Robanus-Maandag, H.P. te Riele et al., Disruption of the mouse mdr1a p-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs, Cell 77 (1994) 491–502. D. De Graaf, R.C. Sharma, E.B. Mechetner, R.T. Schimke, I.B. Roninson, P-glycoprotein confers methotrexate resistance in 3T6 cells with deficient carrier-mediated methotrexate uptake, Proc. Natl. Acad. Sci. USA 93 (1996) 11238– 11242. A.H. Dickenson, The roles of spinal receptors in nociceptive responses, in: S.D. Brain, P.K. Moore (Eds.), Pain and ¨ Neurogenic Inflammation, Birkhauser, Basel, 1999, pp. 23– 38. S. Rivest, How circulating cytokines trigger the neural circuits that control the hypothalamic–pituitary–adrenal axis, Psychoneuroendocrinology 26 (2001) 761–788. S.H. Ferreira, B.B. Lorenzetti, A.F. Bristow, S. Poole, Interleukin-1b as a potent hyperalgesic agent antagonized by a tripeptide analogue, Nature 334 (1988) 698–700. F.Q. Cunha, B.B. Lorenzetti, S. Poole, S.H. Ferreira, Interleukin-8 as a mediator of sympathetic pain, Br. J. Pharmacol. 104 (1991) 765–767.

1001

[63] M.N. Perkins, D. Kelly, A.J. Davis, Bradykinin B 1 and B 2 receptor mechanisms and cytokine-induced hyperalgesia in the rat, Can. J. Physiol. Pharmacol. 73 (1994) 832–836. [64] L.R. Watkins, E.P. Weirtelak, L.E. Goehler, K.P. Smith, D. Martin, S.F. Maier, Characterization of cytokine-induced hyperalgesia, Brain Res. 654 (1994) 15–26. [65] L.R. Watkins, L.E. Goehler, J. Relton, M.T. Brewer, S.F. Maier, Mechanisms of tumor necrosis factor-alpha (TNFalpha) hyperalgesia, Brain Res. 692 (1995) 244–250. [66] M.N. Perkins, Interactions between kinins and the inflammatory pain process, in: S.D. Brain, P.K. Moore (Eds.), Pain and ¨ Neurogenic Inflammation, Birkhauser, Basel, 1999, pp. 103– 114. [67] J.C. Fernandes, J. Martel-Pelletier, J.P. Pelletier, The role of cytokines in osteoarthritis pathophysiology, Biorheology 39 (2002) 237–246. [68] W.A. Banks, L. Ortiz, S.R. Plotkin, A.J. Kastin, Human interleukin (IL) 1 alpha, murine IL-1 alpha and murine IL-1 beta are transported from blood to brain in the mouse by a shared saturable mechanism, J. Pharmacol. Exp. Ther. 259 (1991) 988–996. [69] E.G. Gutierrez, W.A. Banks, A.J. Kastin, Murine tumor necrosis factor alpha is transported from blood to brain in the mouse, J. Neuroimmunol. 47 (1993) 169–176. [70] S.J. Hopkins, N.J. Rothwell, Cytokines and the nervous system I: expression and recognition, Trends Neurosci. 18 (1995) 83–88. [71] L.G. LeMay, A.J. Vander, M.J. Kluger, Role of interleukin 6 in fever in rats, Am. J. Physiol. 258 (1990) R798–R803. [72] A.L. Cooper, N.J. Rothwell, Mechanisms of early and late hypermetabolism and fever after localized tissue injury, Am. J. Physiol. 261 (1991) E698–E705. [73] C.D. Breder, C.A. Dianrello, C.B. Saper, Interleukin-1 immunoreactive innervation of the human hypothalamus, Science 240 (1988) 321–324. [74] S. Gatti, T. Bartfai, Induction of tumor necrosis factor alpha mRNA in the brain after peripheral endotoxin treatment comparison with interleukin-1 family and interleukin-6, Brain Res. 624 (1993) 291–294. [75] L.I. Romero, G. Schettini, R.M. Lechan, C.A. Dinarello, S. Reichlin, Bacterial lipopolysaccharide induction of IL-6 in rat telencephalic cells is mediated in part by IL-1, Neuroendocrinology 57 (1993) 892–897. [76] B. Schobitz, E.R. de Kloet, W. Sutanto, F. Holsboer, Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain, Eur. J. Neurosci. 5 (1993) 1426–1435. [77] N. Godessart, S.L. Kunkel, Chemokines in autoimmune disease, Curr. Opin. Immunol. 13 (2001) 670–675. [78] D. Rossi, A. Zlotnik, The biology of chemokines and their receptors, Annu. Rev. Immunol. 18 (2000) 217–242. [79] M. Locati, U. Deuschle, M.L. Massardi, F.O. Martinez, M. Sironi, S. Sozzani, T. Bartfai, A. Mantovani, Analysis of the gene expression profile activated by the CC chemokine ligand 5 / RANTES and by lipopolysaccharide in human monocytes, J. Immunol. 168 (2002) 3557–3562. [80] J. Aliberti, C. Reis e Sousa, M. Schito, S. Hieny, T. Wells,

1002

[81]

[82]

[83]

[84]

[85] [86]

[87]

[88]

[89]

[90]

[91] [92]

[93] [94]

[95]

[96]

[97]

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006 G.B. Huffnagle, A. Sher, CCR5 provides a signal for microbial-induced production of IL-12 by CD8a 1 dendritic cells, Nat. Immunol. 1 (2000) 83–87. M.C. Braun, E. Lahey, B.L. Kelsall, Selective suppression of IL-12 production by chemoattractants, J. Immunol. 164 (2000) 3009–3017. A. Bajetto, R. Bonavia, S. Barbero, G. Schettini, Characterization of chemokines and their receptors in the central nervous system: physiopathological implications, J. Neurochem. 82 (2002) 1311–1329. T.A. Springer, Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration, Annu. Rev. Physiol. 57 (1995) 827–872. ´ M.C. Cid, M. Cebrian, C. Font, B. Coll-Vinent, J. ´ ´ ´ Hernandez-Rodrıguez, J. Esparza, A. Urbano-Marquez, J.M. Grau, Cell adhesion molecules in the development of inflammatory infiltrates in giant cell arteritis, Arthritis Rheum. 43 (2000) 184–194. S.M. Albelda, C.W. Smith, P.A. Ward, Adhesion molecules and inflammatory injury, FASEB J. 8 (1994) 504–512. X. Wang, G.Z. Feuerstein, Induced expression of adhesion molecules following focal brain ischemia, J. Neurotrauma 12 (1995) 825–832. E.F. Howard, Q. Chen, C. Cheng, J.E. Carroll, D. Hess, NF-kB is activated and ICAM-1 gene expression is upregulated during reoxygenation of human brain endothelial cells, Neurosci. Lett. 248 (1998) 199–203. J.M. Harlan, R.K. Winn, Leukocyte–endothelial interactions: clinical trials of anti-adhesion therapy, Crit. Care Med. 30 (2002) S214–S219. A.J. Huang, J.E. Manning, T.M. Bandak, M.C. Ratau, K.R. Hanser, S.C. Silverstein, Endothelial cell cytosolic free calcium regulates neutrophil migration across monolayers of endothelial cells, J. Cell Biol. 120 (1993) 1371–1380. R. Milner, I.L. Campbell, Developmental regulation of b1 integrins during angiogenesis in the central nervous system, Mol. Cell. Neurosci. 20 (2002) 616. L.S. Jones, Integrins: possible functions in the adult CNS, Trends Neurosci. 19 (1996) 68–72. J.K. Pinkstaff, J. Detterich, J. Lynch, C. Gall, Integrin subunit gene expression is regionally differentiated in adult brain, J. Neurosci. 19 (1999) 1541–1556. T.A. Springer, Adhesion receptors of the immune system, Nature 346 (1990) 425–434. R. Sobel, J. Hinojoza, A. Maeda, M. Chen, Endothelial cell integrin laminin receptor expression in multiple sclerosis lesions, Am. J. Pathol. 153 (1998) 405–415. J.E. Merrill, S.P. Murphy, Inflammatory events at the blood– brain barrier: regulation of adhesion molecules, cytokines, and chemokines by reactive nitrogen and oxygen species, Brain, Behav. Immun. 11 (1997) 245–263. Z.S. Galis, J.J. Khatri, Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly, Circ. Res. 90 (2002) 251–262. H. Birkedal-Hansen, Role of cytokines and inflammatory mediators in tissue destruction, J. Periodontal Res. 28 (1993) 500–510.

[98] R. Paul, S. Lorenzl, U. Koedel, B. Sporer, U. Vogel, M. Frosch, H.W. Pfister, Matrix metalloproteinases contribute to the blood–brain barrier disruption during bacterial meningitis, Ann. Neurol. 44 (1998) 592–600. [99] S. Mun-Bryce, G.A. Rosenberg, Gelatinase B modulates selective opening of the blood–brain barrier during inflammation, Am. J. Physiol. 274 (1998) R1203–R1211. [100] S. Mun-Bryce, G.A. Rosenberg, Matrix metalloproteinases in cerebrovascular disease, J. Cereb. Blood Flow Metab. 18 (1998) 1163–1172. [101] Z.S. Galis, M. Muszynski, G.K. Sukhova, E. Simon-Morrissey, E.N. Unemori, M.W. Lark, E. Amento, P. Libby, Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion, Circ. Res. 75 (1994) 181–189. [102] P. Libby, Z.S. Gallis, Cytokines regulate genes involved in atherosclerosis, in: F. Numano, R.W. Wissler (Eds.), Atherosclerosis III: Recent Advances in Atherosclerosis Research, New York Academy of Sciences, New York, 1995, pp. 158–170. [103] A.E. McEarchern, E.R. Shelton, S. Bhakta, R. Obernolte, C. Back, P. Zuppan, J. Fujisaka, R.W. Aldrich, K. Jarnagin, Expression cloning of a rat B 2 bradykinin receptor, Proc. Natl. Acad. Sci. USA 88 (1991) 7724–7728. [104] J.M. Hall, Bradykinin receptors: pharmacological properties and biological roles, Pharmacol. Ther. 56 (1992) 131–190. [105] J.F. Hess, J.A. Borkowski, G.S. Young, C.D. Strader, R.W. Ranson, Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor, Biochem. Biophys. Res. Commun. 184 (1992) 260–268. [106] D. Armstrong, Pain, in: E.G. Erdos, A.F. Wilde (Eds.), Bradykinin, Kallidin, and Kallikrein, Handbook of Experimental Pharmacology, vol. 25, Springer-Verlag, Berlin, 1970, pp. 434–515. [107] R.W. Coleman, P.Y. Wong, Kallikrein–kinin system in pathologic conditions, in: E.G. Erdos, A.F. Wilde (Eds.), Bradykinin, Kallidin, And Kallikrein, Handbook of Experimental Pharmacology, vol. 25, Springer-Verlag, Berlin, 1970, pp. 569–607. ´ Pharmacology of bradykinin and [108] D. Regoli, J. Barabe, related kinins, Am. Soc. Pharmacol. Exp. Ther. 32 (1980) 1–46. [109] S. Oh-Ishi, I. Hayashi, I. Utsunomiya, M. Hayashi, K. Yamaki, A. Yamasu, T. Nakano, Roles of kallikrein–kinin system in acute inflammation: studies on high- and lowmolecular weight kininogens-deficient rats (B / N-Katholiek strain), Agents Actions 21 (1987) 384–386. [110] G.M. Burgess, J. Mullaney, M. McNei, P. Dunn, H.P. Rang, Second messengers involved in the action of bradykinin on cultured sensory neurons, J. Neurosci. 9 (1989) 3314–3325. [111] A. Rueff, A. Dray, Sensitization of peripheral afferent fibres in the in vitro neonatal rat spinal cord-tail by bradykinin and prostaglandins, Neuroscience 54 (1993) 527–535. [112] K. Walker, M. Perkins, A. Dray, Kinins and kinin receptor systems in the nervous system, Neurochem. Int. 26 (1995) 1–16. [113] R.E. Lewis, S.R. Childers, M.I. Phillips, (125I) Tyr-brady-

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

[114]

[115]

[116]

[117]

[118]

[119]

[120]

[121]

[122]

[123]

[124]

[125]

[126]

[127]

[128]

kinin binding in primary rat brain cultures, Brain Res. 346 (1985) 263–272. R.M. Snider, E. Richelson, Bradykinin receptor mediated cyclic GMP formation in a nerve cell population (murine neuroblastoma, clone NIE-115), J. Neurochem. 43 (1984) 1749–1754. D.J. Campbell, A. Kladis, A.M. Duncan, Bradykinin peptides in kidney, blood and other tissues of the rat, Hypertension 21 (1993) 155–165. E. Hosli, L. Hosli, Autoradiographic localization of binding sites for neuropeptide Y and bradykinin on astrocytes, Neuroreport 4 (1993) 159–162. M. Wahl, C. Gorlach, T. Hortobagyi, Z. Benyo, Effects of bradykinin in the cerebral circulation, Acta Physiol. Hung. 86 (1999) 155–160. V. Parpura, T.A. Basarsky, F. Liu, K. Jeftnija, S. Jeftnija, P.G. Haydon, Glutamate-mediated astrocyte-neuron signaling, Nature 369 (1994) 744–747. R.P. Phipps, S.H. Stein, R.L. Roper, A new view of prostaglandin-E regulation of the immune response, Immunol. Today 12 (1991) 349–352. E.J. Goetzl, S. An, W.L. Smith, Specificity of expression and effects of eicosanoid mediators in normal physiology and human diseases, FASEB J. 9 (1995) 1051–1058. S. Moncada, R.J. Flower, J.R. Vane, Prostaglandins, prostacyclin and thromboxane A2, in: A.G. Gilman, L.S. Goodman, T.W. Rall, F. Murad (Eds.), The Pharmacological Basis of Therapeutics, Macmillan, New York, 1985, pp. 660–673. S.G. Harris, J. Padilla, L. Koumas, D. Ray, R.P. Phipps, Prostaglandins as modulators of immunity, Trends Immunol. 23 (2002) 144–150. B. Hinz, K. Brune, A. Pahl, Prostaglandin E(2) upregulates cyclooxygenase-2 expression in lipopolysaccharide-stimulated RAW 264.7 macrophages, Biochem. Biophys. Res. Commun. 272 (2000) 744–748. R. Ikegami, Y. Sugimoto, E. Segi, M. Katsuyama, H. Karahashi, F. Amano, T. Maruyama, H. Yamane, S. Tsuchiya, A. Ichikawa, The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by lipopolysaccharide in C3H / HeN peritoneal macrophages, J. Immunol. 166 (2001) 4689–4696. G. Katsuura, P.E. Gottschall, R.R. Dahl, A. Arimura, Interleukin-1 beta increases prostaglandin E2 in rat astrocyte cultures: modulatory effect of neuropeptides, Endocrinology 124 (1989) 3125–3127. V. Rettori, M. Gimeno, K. Lyson, S.M. McCann, Nitric oxide mediates norepinephrine-induced prostaglandin E2 release from the hypothalamus, Proc. Natl. Acad. Sci. USA 89 (1992) 11543–11546. S. Nogawa, F. Zhang, M.E. Ross, C. Iadecola, Cyclooxygenase-2 gene expression in neurons contributes to ischemic brain damage, J. Neurosci. 17 (1997) 2746–2755. K.S. Mark, W.J. Trickler, D.W. Miller, Tumor necrosis factor-a induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells, J. Pharmacol. Exp. Ther. 297 (2001) 1051–1058.

1003

[129] E. Vegeto, C. Bonincontro, G. Pollio, A. Sala, S. Viappiani, F. Nardi, A. Brusadelli, B. Viviani, P. Ciana, A. Maggi, Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia, J. Neurosci. 21 (2001) 1809– 1818. [130] K. Yamagata, K. Matsumura, W. Inoue, T. Shiraki, K. Suzuki, S. Yasuda, H. Sugiura, C. Cao, Y. Watanabe, S. Kobayashi, Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever, J. Neurosci. 21 (2001) 2669–2677. [131] K. Yamagata, K.I. Andreasson, W.E. Kaufmann, C.A. Barnes, P.F. Worley, Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids, Neuron 11 (1993) 371–386. [132] J. Adams, Y. Collac¸o-Moraes, J. De Belleroche, Cyclooxygenase-2 induction in cerebral cortex: an intracellular response to synaptic excitation, J. Neurochem. 66 (1996) 6–13. [133] V.L. Marcheselli, N.G. Bazan, Sustained induction of prostaglandin endoperoxide synthase-2 by seizures in hippocampus, J. Biol. Chem. 271 (1996) 24794–24799. [134] P. Repovic, E.N. Benveniste, Prostaglandin E2 is a novel inducer of oncostatin-M expression in macrophages and microglia, J. Neurosci. 22 (2002) 5334–5343. [135] N.J. Van Wagoner, C. Choi, P. Repovic, E.N. Benveniste, Oncostatin M regulation of interleukin-6 expression in astrocytes: biphasic regulation involving the mitogen-activated protein kinases ERK1 / 2 and p38, J. Neurochem. 75 (2000) 563–575. [136] K. Ruprecht, T. Kuhlmann, F. Seif, V. Hummel, N. Kruse, W. Bruck, P. Rieckmann, Effects of oncostatin M on human cerebral endothelial cells and expression in inflammatory brain lesions, J. Neuropathol. Exp. Neurol. 60 (2001) 1087–1098. [137] K. Murase, P.D. Ryu, M. Randic, Tachykinins modulate multiple ionic conductances in voltage-clamped rat spinal dorsal horn neurons, J. Neruophys. 61 (1989) 854–865. [138] J.A. Harris, Using c-fos as a neural marker of pain, Brain Res. Bull. 45 (1998) 1–8. [139] B. Pernow, Substance P, Pharmacol. Rev. 5 (1983) 85–141. [140] Z. Wiesenfeld-Hallin, T. Hokfelt, J.M. Lundberg, W.G. Forssmann, M. Reinecke, F.A. Tschopp, J.A. Fischer, Immunoreactive calcitonin gene-regulated peptide and substance P coexist in sensory neurons of the spinal cord and interact in spinal behavioral responses of the rat, Neurosci. Lett. 52 (1984) 199–204. [141] A.H. Dickenson, NMDA receptor antagonists as analgesics, in: H.L. Fields, J.C. Liebeskind (Eds.), Pharmacological Approaches To the Treatment of Chronic Pain: New Concepts and Critical Issues, IASP Press, Seattle, WA, 1994, pp. 173–187. [142] A.H. Dickenson, Spinal cord pharmacology of pain, Br. J. Anaesth. 75 (1995) 193–200. [143] A.H. Dickenson, J.-M. Besson (Eds.), The Pharmacology of Pain, Springer-Verlag, Berlin, 1997. [144] G. Collingridge, W. Singer, Excitatory amino acid receptors

1004

[145]

[146]

[147]

[148]

[149]

[150] [151]

[152]

[153]

[154]

[155]

[156]

[157]

[158]

[159]

[160]

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006 and synaptic plasticity, Trends Pharm. Sci. 11 (1990) 290– 296. C. Matute, K. Gutierrez-Igarza, C. Rio, R. Miledi, Glutamate receptors in astrocytic end-feet, Neuroreport 5 (1994) 1205–1208. I.A. Krizbai, M.A. Deli, A. Pestenacz, L. Siklos, C.A. Szabo, I. Andras, F. Joo, Expression of glutamate receptors on cultured cerebral endothelial cells, J. Neurosci. Res. 54 (1998) 814–819. P. Morley, D.L. Small, C.L. Murray, G.A. Mealing, M.O. Poulter, J.P. Durkin, D.B. Stanimirovic, Evidence that functional glutamate receptors are not expressed on rat or human cerebromicrovascular endothelial cells, J. Cereb. Blood Flow Metab. 18 (1998) 396–406. C.D. Collard, K.A. Park, M.C. Montalto, S. Alapati, J.A. Buras, G.L. Stahl, S.P. Colgan, Neutrophil-derived glutamate regulates vascular endothelial barrier function, J. Biol. Chem. 277 (2002) 14801–14811. F. St’astny, M. Schwendt, V. Lisy, D. Jezova, Main subunits of ionotropic glutamate receptors are expressed in rat brain microvessel, Neurol. Res. 24 (2002) 93–96. D.B. Miller, J.P. O’Callaghan, Neuroendocrine aspects of the response to stress, Metabolism 51 (2002) 5–10. A.V. Turnbull, C.L. Rivier, Regulation of the hypothalamic– pituitary–adrenal axis by cytokines: actions and mechanisms of action, Physiol. Rev. 79 (1999) 1–71. I.J. Elenkov, G.P. Chrousos, Stress hormones, proinflammatory and inflammatory cytokines, and autoimmunity, Ann. N. Y. Acad. Sci. 966 (2002) 290–303. J.I. Webster, L. Tonelli, E.M. Sternberg, Neuroendocrine regulation of immunity, Annu. Rev. Immunol. 20 (2002) 125–163. F.R. Haselton, S.N. Mueller, R.E. Howell, E.M. Levine, A.P. Fishman, Chromatographic demonstration of reversible changes in endothelial permeability, J. Appl. Physiol. 67 (1989) 2032–2048. E. Dejana, Endothelial adherens junctions: implications in the control of vascular permeability and angiogenesis, J. Clin. Invest. 100 (1997) S7–S10. G.P. Nieuw Amerongen, S. van Delft, M.A. Vermeer, J.G. Collard, V.W. van Hinsbergh, Activation of RhoA by thrombin in endothelial hyperpermeability: role of Rho kinase and protein tyrosine kinases, Circ. Res. 87 (2000) 335–340. A.L. Baldwin, G. Thurston, Mechanics of endothelial cell architechture and vascular permeability, Crit. Rev. Biomed. Eng. 29 (2001) 247–278. H.E. de Vries, M.C. Blom-Roosemalen, M. van Oosten, A.G. de Boer, T.J. van Berkel, D.D. Breimer, J. Kuiper, The influence of cytokines on the integrity of the blood–brain barrier in vitro, J. Neuroimmunol. 64 (1996) 37–43. S.M. Gloor, A. Weber, N. Adachi, K. Frei, Interleukin-1 modulates protein tyrosine phosphatase activity and permeability of brain endothelial cells, Biochem. Biophys. Res. Commun. 239 (1997) 804–809. S. Citi, Protein kinase inhibitors prevent junction dissociation induced by low extracelllular calcium in MDCK epithelial cells, J. Cell Biol. 117 (1992) 169–178.

[161] T. Volberg, Y. Zick, R. Dror, I. Sabanay, C. Gilon, A. Levitzki, B. Geiger, The effect of tyrosine-specific protein phosphorylation on the assembly of adherens-type junctions, EMBO J. 11 (1992) 1733–1742. [162] J.M. Staddon, K. Herrenknecht, C. Smales, L.L. Rubin, Evidence that tyrosine phosphorylation may increase tight junction permeability, J. Cell Sci. 108 (1995) 609–619. [163] S.J. Bolton, D.C. Anthony, V.H. Perry, Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood–brain barrier breakdown in vivo, Neuroscience 86 (1998) 1245–1257. [164] A.M. Blamire, D.C. Anthony, B. Rajagopalan, N.R. Sibson, V.H. Perry, P. Styles, Interleukin-1 beta-induced changes in blood–brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study, J. Neurosci. 20 (2000) 8153– 8159. [165] M. Wachtel, M.F. Bolliger, H. Ishihara, K. Frei, H. Bluethmann, S.M. Gloor, Down-regulation of occludin expression in astrocytes by tumour necrosis factor (TNF) is mediated via TNF type-1 receptor and nuclear factor-kappa B activation, J. Neurochem. 78 (2001) 155–162. [166] L. Descamps, R. Cecchelli, G. Torpier, Effects of tumor necrosis factor on receptor-mediated endocytosis and barrier functions of blood–brain capillary endothelial cell monolayers, J. Neuroimmunol. 74 (1997) 173–184. [167] H.A. Edens, C.A. Parkos, Modulation of epithelial and endothelial paracellular permeability by leukocytes, Adv. Drug Deliv. Rev. 41 (2000) 315–328. [168] L.A. Boven, J. Middel, J. Verhoef, C.J. De Groot, H.S. Nottet, Monocyte infiltration is highly associated with loss of the tight junction protein zonula occludens in HIV-1associated dementia, Neuropathol. Appl. Neurobiol. 26 (2000) 356–360. [169] C.A. Partridge, J.J. Jeffrey, A.B. Malik, A 96-kDa gelatinase induced by TNF-alpha contributes to increased microvascular endothelial permeability, Am. J. Physiol. 265 (1993) L438–L447. [170] M. Wachtel, K. Frei, E. Ehler, A. Fontana, K. Winterhalter, S.M. Gloor, Occludin proteolysis and increased permeability in endothelial cells through tyrosine phosphatase inhibition, J. Cell Sci. 112 (1999) 4347–4356. [171] J.S. Alexander, J.W. Elrod, Extracellular matrix, junctional integrity, and matrix metalloproteinase interactions in endothelial permeability regulation, J. Anat. 200 (2002) 561– 574. [172] M.H. Sarker, D.E. Hu, P.A. Fraser, Acute effects of bradykinin on cerebral microvascular permeability in the anaesthetized rat, J. Physiol. 528 (2000) 177–187. [173] E. Sanovich, R.T. Bartus, P.M. Friden, R.L. Dean, H.Q. Le, M.W. Brightman, Pathway across blood–brain barrier opened by the bradykinin agonist, RMP-7, Brain Res. 705 (1995) 125–135. [174] A. Prat, K. Biernacki, S. Pouly, J. Nalbantoglu, R. Couture, J.P. Antel, Kinin B1 receptor expression and function on human brain endothelial cells, J. Neuropathol. Exp. Neurol. 59 (2000) 896–906.

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006 [175] C. Cioni, D. Renzi, A. Calabro, P. Annunziata, Enhanced secretion of substance P by cytokine-stimulated rat brain endothelium cultures, J. Neuroimmunol. 84 (1998) 76–85. [176] R.E. Catalan, A.M. Martinez, M.D. Aragones, I. Fernandez, Substance P stimulates translocation of protein kinase C in brain microvessels, Biochem. Biophys. Res. Commun. 164 (1989) 595–600. [177] M.J. Moreno, J.A. Terron, D.B. Stanimirovic, H. Doods, E. Hamel, Characterization of calcitonin gene-regulated peptide (CGRP) receptors and their receptor-activity-modifying proteins (RAMPs) in human brain microvascular and astroglial cells in culture, Neuropharmacology 42 (2002) 270–280. [178] A. Baethmann, K. Maier-Hauff, O. Kempski, A. Unterberg, M. Wahl, L. Schurer, Mediators of brain edema and secondary brain damage, Crit. Care Med. 16 (1988) 972– 978. [179] I. Westergren, B. Nystrom, A. Hamberger, C. Nordborg, B.B. Johansson, Concentrations of amino acids in extracellular fluid after opening of the blood–brain barrier by intracarotid infusion of protamine sulfate, J. Neurochem. 62 (1994) 159–165. [180] W.G. Mayhan, S.P. Didion, Glutamate-induced disruption of the blood–brain barrier in rats, Stroke 27 (1996) 965–970. [181] C. Bolton, C. Paul, MK-801 limits neurovascular dysfunction during experimental allergic encephalomyelitis, J. Pharm. Exp. Ther. 282 (1997) 397–402. [182] K. Mori, M. Maeda, M. Miyazaki, H. Iwase, Effects of mild and moderate hypothermia on cerebral metabolism and glutamate in an experimental head injury, Acta Neurochir. Suppl. (Wien) 71 (1998) 222–224. [183] Y. Kustova, A. Grinberg, A.S. Basile, Increased blood– brain barrier permeability in LP-BM5-infected mice is mediated by neuroexcitatory mechanisms, Brain Res. 839 (1999) 153–163. [184] K. Nishida, S.P. Markey, P. Skolnick, A.S. Basile, Y. Sei, Increases in brain platelet activating factor were inhibited by the N-methyl-D-aspartate antagonist MK-801 in mice infected with the LP-BM5 murine leukemia virus, J. Neurochem. 66 (1996) 433–435. [185] S.J. Bolton, V.H. Perry, Differential blood–brain barrier breakdown and leukocyte recruitment following excitotoxic lesions in juvenile and adult rats, Exp. Neurol. 154 (1998) 231–240. [186] P.J. Rosch, Stress and illness, J. Am. Med. Assoc. 242 (1979) 427–428. [187] V. Mei-Tal, S. Meyerowitz, G.L. Engel, The role of psychological process in a somatic disorder: multiple sclerosis. 1. The emotional setting of illness onset and exacerbation, Psychosom. Med. 32 (1970) 67–86. [188] S. Warren, S. Greenhill, K.G. Warren, Emotional stress and the development of multiple sclerosis: case control evidence of a relationship, J. Chronic Dis. 35 (1982) 821–831. [189] D.S. Goodin, G.C. Ebers, K.P. Johnson, M. Rodriguez, W.A. Sibley, J.S. Wolinsky, The relationship of MS to physical trauma and psychological stress, Neurology 52 (1999) 1737–1745.

1005

[190] S.J. Galli, New concepts about the mast cell, New Engl. J. Med. 328 (1993) 257–265. [191] T.C. Theoharides, Mast cells: the immune gate to the brain, Life Sci. 46 (1990) 607–617. [192] K. Karalis, H. Sano, J. Redwine, S. Listwak, R.L. Wilder, G.P. Chrousos, Autocrine or paracrine inflammatory actions of corticotrophin-releasing hormone in vivo, Science 254 (1991) 421–423. [193] T.C. Theoharides, L. Singh, W. Boucher, X. Pang, R. Letourneau, E. Webster, G. Chrousos, Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its pro-inflammatory effects, Endocrinology 139 (1998) 403–413. [194] P. Esposito, D. Gheorghe, K. Kandere, X. Pang, R. Connolly, S. Jacobson, T.C. Theoharides, Acute stress increases permeability of the blood–brain barrier through activation of brain mast cells, Brain Res. 888 (2001) 117–127. [195] H.E. de Vries, M.C. Blom-Roosemalen, A.G. de Boer, T.J. van Berkel, D.D. Breimer, J. Kuiper, Effect of endotoxin on permeability of bovine cerebral endothelial cell layers in vitro, J. Pharmacol. Exp. Ther. 277 (1996) 1418–1423. [196] R.W. Gregg, J.M. Molepo, V.J.A. Monpetit, N.Z. Mikael, D. Redmond, M. Gadia, D.J. Stewart, Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues and morphologic evidence of toxicity, J. Clin. Oncol. 10 (1992) 795–803. [197] T. Minami, J. Okazaki, A. Kawabata, R. Kuroda, Y. Okazaki, Penetration of cisplatin into mouse brain by lipopolysaccharide, Toxicology 130 (1998) 107–113. [198] G.M. Higa, T.C. Wise, E.B. Crowell, Severe, disabling neurologic toxicity following cisplatin retreatment, Ann. Pharmacother. 29 (1995) 134–137. [199] T. Anda, H. Yamashita, H. Khalid, K. Tsutsumi, H. Fujita, Y. Tokunaga, S. Shibata, Effect of tumor necrosis factoralpha on the permeability of bovine brain microvessel endothelial cell monolayers, Neurol. Res. 19 (1997) 369– 376. [200] D. Wu, W.M. Pardridge, Neuroprotection with noninvasive neurotrophin delivery to the brain, Proc. Natl. Acad. Sci. USA 96 (1999) 254–259. [201] B.W. Song, H.V. Vinters, D. Wu, W.M. Pardridge, Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood–brain barrier delivery vector, J. Pharmacol. Exp. Ther. 301 (2002) 605–610. [202] D. Wu, B.W. Song, H.V. Vinters, W.M. Pardridge, Pharmacokinetics and brain uptake of biotinylated basic fibroblast growth factor conjugated to a blood–brain barrier drug delivery system, J. Drug Target. 10 (2002) 239–245. [203] R.J. Boado, H. Tsukamoto, W.M. Pardridge, Drug delivery of antisense molecules to the brain for treatment of Alzheimer’s disease and cerebral AIDS, J. Pharm. Sci. 87 (1998) 1308–1315. [204] X.B. Li, G.S. Liao, Y.Y. Shu, S.X. Tang, Brain delivery of biotinylated NGF bounded to an avidin–transferrin conjugate, J. Nat. Toxins 9 (2000) 73–83.

1006

A.M. Wolka et al. / Advanced Drug Delivery Reviews 55 (2003) 987–1006

[205] K.F. Swaiman, Hallervorden–Spatz syndrome and brain iron metabolism, Arch. Neurol. 48 (1991) 1285–1293. [206] P. Jenner, Oxidative damage in neurodegenerative disease, Lancet 344 (1994) 796–798. [207] P. Aisen, M. Wessling-Resnick, E.A. Leibold, Iron metabolism, Curr. Opin. Chem. Biol. 3 (1999) 200–206. [208] Z.M. Qian, Q. Wang, Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders, Brain Res. Rev. 27 (1998) 257–267. [209] Z.M. Qian, X. Shen, Brain iron transport and neurodegeneration, Trends Mol. Med. 7 (2001) 103–108. [210] K.H. Dykstra, A. Arya, D.M. Arriola, P.M. Bungay, P.F. Morrison, R.L. Dedrick, Microdialysis study of zidovudine (AZT) transport in rat brain, J. Pharmacol. Exp. Ther. 267 (1993) 1227–1236. [211] S.L. Wong, K. van Belle, R.J. Sawchuk, Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid / cerebrospinal fluid in the rabbit: investigation of the inhibitory effect of probenecid utilizing microdialysis, J. Pharmacol. Exp. Ther. 264 (1993) 899– 909. [212] Y. Wang, Y. Wei, R.J. Sawchuk, Zidovudine transport within the rabbit brain during intracerebroventricular administration and the effect of probenecid, J. Pharm. Sci. 86 (1997) 1484–1493. [213] Y. Deguchi, Y. Yokoyama, T. Sakamoto, H. Hayashi, T. Naito, S. Yamada, R. Kimura, Brain distribution of 6mercaptopurine is regulated by the efflux transport system in the blood–brain barrier, Life Sci. 66 (2000) 649–662. [214] S.M. Dombrowski, S.Y. Desai, M. Marroni, L. Cucullo, K. Goodrich, W. Bingman, M.R. Mayberg, L. Bengez, D. Janigro, Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy, Epilepsia 42 (2001) 1501–1506. [215] R.A. Felix, M.A. Barrand, P-glycoprotein expression in rat brain endothelial cells: evidence for regulation by transient oxidative stress, J. Neurochem. 80 (2002) 64–72. [216] M. Piquette-Miller, A. Pak, H. Kim, R. Anari, A. Shahzamani, Decreased expression and activity of P-

[217]

[218]

[219]

[220]

[221]

[222]

[223]

[224]

glycoprotein in rat liver during acute inflammation, Pharm. Res. 15 (1998) 706–711. M. Sukhai, A. Yong, A. Pak, M. Piquette-Miller, Decreased expression of P-glycoprotein in interleukin-1 beta and interleukin-6 treated rat hepatocytes, Inflamm. Res. 50 (2001) 362–370. G. Hartmann, A.K. Cheung, M. Piquette-Miller, Inflammatory cytokines, but not bile acids, regulate expression of murine hepatic anion transporters in endotoxemia, J. Pharmacol. Exp. Ther. 303 (2002) 273–281. T. Sakaeda, T.J. Siahaan, K.L. Audus, V.J. Stella, Enhancement of transport of D-melphalan analogue by conjugation with L-glutamate across bovine brain microvessel endothelial cell monolayers, J. Drug Target. 8 (2000) 195–204. T. Sakaeda, Y. Tada, T. Sugawara, T. Ryu, F. Hirose, T. Yoshikawa, K. Hirano, L. Kupczyk-Subotkowska, T.J. Siahaan, K.L. Audus, V.J. Stella, Conjugation with L-glutamate for in vivo brain drug delivery, J. Drug Target. 9 (2001) 23–37. D.F. Emerich, R.L. Dean, C. Osborn, R.T. Bartus, The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood–brain barrier: from concept to clinical evaluation, Clin. Pharmacokinet. 40 (2001) 105–123. R.L. Dean, D.F. Emerich, B.P. Hasler, R.T. Bartus, Cereport (RMP-7) increases carboplatin levels in brain tumors after pretreatment with dexamethasone, Neuro-oncology 1 (1999) 268–274. R.T. Bartus, P. Snodgrass, J. Marsh, M. Agostino, A. Perkins, D.F. Emerich, Intravenous cereport (RMP-7) modifies topographic uptake profile of carboplatin within rat glioma and brain surrounding tumor, elevates platinum levels, and enhances survival, J. Pharmacol. Exp. Ther. 293 (2000) 903–911. D.F. Emerich, R.L. Dean, J. Marsh, M. Pink, D. Lafreniere, P. Snodgrass, R.T. Bartus, Intravenous cereport (RMP-7) enhances delivery of hydrophilic chemotherapeutics and increases survival in rats with metastatic tumors in the brain, Pharm. Res. 17 (2000) 1212–1219.