Current Pharmaceutical Design - Volume 14, Issue 16, 2008

Over 100 years ago, experiments were conducted that showed an inability of selected blood-borne substances to enter the central nervous system (CNS). These experiments served as the basis of the concept of a blood-brain barrier (BBB). Research in subsequent decades expanded our understanding of the blood-brain barrier. The last 40 years in particular has elucidated the ultrastructural basis for the restrictive aspects of the BBB, shown that the BBB is endowed with a myriad of transporters, is composed of endothelial, epithelial, and tanycytic arms, regulates the flux of immune cell trafficking into the brain, and secretes a wide number of substances [1]. Transport systems supply the brain with glucose, amino acids, vitamins, electrolytes, and minerals and remove from the brain toxins, both endogenous and exogenous. The BBB regulates an exchange of informational molecules between the CNS and peripheral tissues. The BBB secretes prostaglandins, nitric oxide, and cytokines into both the blood and the CNS. All these activities of the BBB are themselves regulated and slave to the needs of the CNS. They help the CNS maintain the homeostatic and nutritive environment critical to survival and provide mechanisms for communication between the brain and peripheral tissues. As such, the BBB is not simply a barrier, but a regulatory interface between the CNS and blood. What happens when some complex function of the BBB fails? Could dysregulation of a function of the BBB cause disease? The role of the BBB in diseases of the CNS has long been appreciated. However, its roles have generally been viewed either in terms of drug delivery across the BBB or as the BBB being targeted by disease processes. But the complexity and importance of the BBB makes it clear that dysregulation or failure of its processes or an inability to respond to the needs of the CNS could lead to disease states. In such a case, the BBB itself becomes the therapeutic target. This special issue examines some of the conditions in which BBB dysfunction seems to play a primary causal role in disease. Although this has been a neglected view, there are clear precedents to such a concept. Disruption of BBB integrity with extremely high blood pressures leads to hypertensive encephalopathy [2] and a deficiency of glucose transporters at the BBB underlies a familial form of mental retardation [3]. This issue also explores the physiological and pathological underpinnings which may predispose the BBB to be a seat of disease. Multiple sclerosis has long been viewed as a classic disease of the BBB [4]. Invasion of the CNS by immune cells is key to the pathophysiology of multiple sclerosis. However, the immune cells do not “leak” across a disrupted BBB. Even in advanced disease, the trafficking of immune cells into the CNS is a highly regulated, multi-staged process, termed diapedesis. Understanding this process will lead to better treatments for multiple sclerosis, as has already occurred with the introduction of anti-alpha 4-integrins. Whereas this improved understanding may help us to keep immune cells out in multiple sclerosis, it may also help us to get more immune cells into the brain; the latter would be desirable after bone marrow transplantation for the treatment of lysosomal storage diseases [5]. We now know that immune cell trafficking occurs normally in healthy adults as part of immunosurveillance. This mostly occurs at the post-capillary venule. Thus, a type of regional specification of the BBB architecture is illustrated. This is recapitulated by pericyte specification in that arteriolar, but not capillary pericytes, typically possess alpha smooth muscle actin [6]. The BBB also shows variation among brain regions in susceptibility to disruption in diabetes [7] and the rate at which informational molecules such as cytokines are transported across the BBB [8]. A disease in which the BBB was thought to be relatively preserved is diabetes mellitus. However, this has changed dramatically in recent years [9]. As reviewed by Huber, several BBB transporters are now known to be altered, including p-glycoprotein and those for insulin and leptin [10]. Huber's review emphasizes recent findings that the vascular BBB also becomes disrupted with time, especially to the smaller vascular marker molecules such as sucrose and inulin. Susceptibility of the BBB to disruption shows a high degree of regional susceptibility in diabetes, again demonstrating that all regions of the BBB are not identical.......

Before entering the central nervous system (CNS) immune cells have to penetrate any one of its barriers, namely either the endothelial blood-brain barrier, the epithelial blood-cerebrospinal fluid barrier or the tanycytic barrier around the circumventricular organs, all of which maintain homeostasis within the CNS. The presence of these barriers in combination with the lack of lymphatic vessels and the absence of classical MHC-positive antigen presenting cells characterizes the CNS as an immunologically privileged site. In multiple sclerosis a large number of inflammatory cells gains access to the CNS parenchyma. Studies performed in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis, have enabled us to understand some of the molecular mechanisms involved in immune cell entry into the CNS. In particular, the realization that α4-integrins play a predominant role in leukocyte trafficking to the CNS has led to the development of a novel drug for the treatment of relapsing-remitting multiple sclerosis, which targets α4-integrin mediated immune cell migration to the CNS. At the same time, the involvement of other adhesion and signalling molecules in this process remains to be investigated and novel molecules contributing to immune cell entry into the CNS are still being identified. The entire process of immune cell trafficking into the CNS is strictly controlled by the brain barriers not only under physiological conditions but also during neuroinflammation, when some barrier properties are lost. Thus, immune cell entry into the CNS critically depends on the unique characteristics of the brain barriers maintaining CNS homeostasis.

The blood-brain barrier becomes a crucial issue in neuronopathic lysosomal storage diseases for three reasons. Firstly, the function of the blood-brain barrier may be compromised in many of the lysosomal storage diseases and this barrier dysfunction may contribute to the neuropathology seen in the diseases and accelerate cell death. Secondly, the substrate reduction therapies, which successfully reduce peripheral lysosomal storage, because of the blood-brain barrier may not have as free an access to brain cells as they do to peripheral cells. And thirdly, enzyme replacement therapy appears to have little access to the central nervous system as the mannose and mannose-6-phosphate receptors involved in their cellular uptake and transport to the lysosome do not appear to be expressed at the adult blood-brain barrier. This review will discuss in detail these issues and their context in the development of new therapeutic strategies.

Pericytes were described nearly 140 years ago by the French scientist Charles-Marie Benjamin Rouget and were referred to as the Rouget cell. The Rouget cell was renamed primarily due to its anatomical location in the endothelium. Pericytes are important cellular constituents of the capillaries and post capillary venules and are located abluminal to the endothelial cells and luminal to parenchymal cells. They deposit elements of the basal lamina and are totally surrounded by this vascular component. Despite many years of investigation since their discovery, the role of this intriguing cell still remains a mystery, in part, due to the difficulty of studying this cell in vivo, due to the difficulty of isolating pure primary pericytes, and due to the lack of a pericyte specific marker. Pericytes are thought to be local regulatory cells and important to the maintenance of homeostasis and hemostasis. In the brain, pericytes are in active communication with the cells of the neurovascular unit and make fine-tuned regulatory adjustments in response to stress stimuli. These adaptations at the vascular level form the basis for functional and phenotypic changes that include differentiation along mesenchymal and neurological lineages, and lend credence to the supposition that pericytes are multipotential stems cells in the adult brain and in other tissues. This review will consider evidence that pericytes are stem cells derived from historical work and from more recent literature, and will attempt to dispel a number of misconceptions about the pericyte that has lead to confusion in the literature. We will also speculate on the importance of pericyte stem cell activity in survival and DNA repair and how dysregulation of pericyte function may lead to disease.

From a complications standpoint, diabetes mellitus is a disease of the vasculature. Diabetics face a considerably higher risk of developing cardiovascular and cerebrovascular diseases. Both large and small blood vessels are susceptible to alterations from diabetes. Endothelial cell dysfunction associated with small vessel (known as microangiopathy) is a primary factor in the development and progression of diabetes-related disabilities, including blindness, kidney failure, and peripheral neuropathy. Recent clinical evidence show that people with diabetes have increased incidences of vascular dementia, ventricular hypertrophy, lacunar infarcts, hemorrhage, and may be a predisposing factor for Alzheimer's disease. However, the effects of diabetes mellitus on the cerebral microvascular are still largely unknown. This communication will review the relationship between diabetes mellitus and changes in cognition with a particular focus on how alterations in blood-brain barrier structure and function may play a long term role in worsened cognitive abilities.

Low-density lipoprotein receptor related protein-1 (LRP) is a member of the low-density lipoprotein (LDL) receptor family which has been linked to Alzheimer's disease (AD) by biochemical and genetic evidence. Levels of neurotoxic amyloid β-peptide (Aβ) in the brain are elevated in AD contributing to the disease process and neuropathology. Faulty Aβ clearance from the brain appears to mediate focal Aβ accumulations in AD. Central and peripheral production of Aβ from Aβ-precursor protein (APP), transport of peripheral Aβ into the brain across the blood-brain barrier (BBB) via receptor for advanced glycation end products (RAGE), enzymatic Aβ degradation, Aβ oligomerization and aggregation, neuroinflammatory changes and microglia activation, and Aβ elimination from brain across the BBB by cell surface LRP; all may control brain Aβ levels. Recently, we have shown that a soluble form of LRP (sLRP) binds 70 to 90 % of plasma Aβ, preventing its access to the brain. In AD individuals, the levels of LRP at the BBB are reduced, as are levels of Aβ binding to sLRP in plasma. This, in turn, may increase Aβ brain levels through a decreased efflux of brain Aβ at the BBB and/or reduced sequestration of plasma Aβ associated with re-entry of free Aβ into the brain via RAGE. Thus, therapies which increase LRP expression at the BBB and/or enhance the peripheral Aβ “sink” activity of sLRP, hold potential to control brain Aβ accumulations, neuroinflammation and cerebral blood flow reductions in AD.

The dramatic increase in the number of obese and overweight persons has spurred interest in control of appetite, body weight, and adiposity. Leptin is the humoral component of a negative feedback loop between adipose tissue and brain. Leptin is secreted from fat in proportion to the degree of adiposity, is transported across the blood-brain barrier (BBB), and acts in the brain to decrease appetite and increase thermogenesis, actions that ultimately decrease adiposity. However, leptin fails as an adipostat because leptin resistance arises in obesity. The BBB transporter is the first part of the feedback loop to fail, producing the so called “peripheral resistance” to leptin. In this sense, obesity is a disease of the BBB. Failure of leptin as an adipostat raises the question of what its primary role is as does its effects on reproduction, bone, immunity, breathing, cognition, and neurogenesis. Kinetics analysis shows that the BBB transporter performs most efficiently at low serum levels of leptin, suggesting that the feedback loop evolved to operate at lower leptin levels than those seen in ideal body weight. We suggest that low levels of serum leptin inform the brain that adipose reserves are adequate to expend calories on functions other than feeding, such as reproduction and the immune system. This feedback loop is short-circuited when an animal enters starvation. Hallmarks of starvation include decreased secretion of leptin by adipose tissue and hypertriglyceridemia. Triglycerides inhibit the transport of leptin across the BBB, thus attenuating the leptin signal across the BBB and providing a mechanism for peripheral leptin resistance. Triglycerides are elevated in both starvation and obesity. We postulate that hypertriglyceridemia evolved as a starvation signal to the brain that acts in part to inhibit the transport of the leptin across the BBB. The hypertriglyceridemia of obesity invokes this aspect of the starvation response, inducing leptin resistance at the BBB. Thus, the BBB plays important roles in both obesity and starvation.

The two main ways for peptides in the peripheral body to enter the brain are by either saturable transport or passive diffusion across the blood-brain barrier (BBB). Saturable transport systems have the advantage of being responsive to physiological and pathological stimuli. Since saturable systems can regulate peptide entry into the brain, they have the potential to play controlling roles in feeding behavior. For therapeutic applications, however, saturable systems have the disadvantage of functioning as a threshold to limit access of large amounts of peptides into the brain. This pharmacological problem presumably would not be encountered for peptides crossing the BBB by passive diffusion, a process dependent on physicochemical properties. Thus, the gatekeeper function of the BBB can be expanded to a primary governing role, especially for entry of ingestive peptides subject to their respective saturable transport systems.

Spinal cord injury (SCI) induces dynamic changes of the blood-spinal cord barrier and even the more distant blood-brain barrier. Besides an immediate increase of paracellular permeability resulting from the direct impact of the injury, the transport systems for selective cytokines undergo regulatory changes. Since many of the transported molecules play essential roles in neuroregeneration, we propose that this altered peripheral tissue / CNS interaction benefits remodeling of the spinal cord and functional recovery after SCI. This review examines the transport of cytokines and neurotrophic factors into the spinal cord, emphasizing the upregulation of two cytokines - tumor necrosis factor α (TNF) and leukemia inhibitory factor (LIF) - during the course of SCI. The increased transport of TNF and LIF after SCI remains saturable and does not coincide with generalized BBB disruption, highlighting a pivotal regulatory role for the bloodspinal cord barrier.

Pain is a complex phenomenon involving both a peripheral innate immune response and a CNS response as well as activation of the hypothalamic-pituitary-adrenal axis. The peripheral innate immune response to injury involves the rapid production and local release of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and IL-6. Recent studies into the CNS response to peripheral chronic inflammatory pain strongly implicates a role for glia, and local synthesis of proinflammatory cytokines and growth factors. A characteristic feature of CNS inflammation is gliosis, in which inflammatory mediators activate glial cells (e.g. astrocytes and microglia, macrophages and leukocytes) which have been shown to induce and maintain hyperalgesia. In addition, inflammatory pain induces changes in blood-brain barrier (BBB) permeability and alters transport of clinically relevant drugs used to treat pain into the brain. Despite the increasing body of evidence for the involvement of glia in chronic pain and the role of glia in maintaining the BBB, few studies have addressed glial/endothelial interactions and the mechanisms by which glia may regulate the BBB during inflammatory pain. Further studies into the cellular mechanisms of glial/endothelial interactions may identify novel therapeutic targets for reversing chronic inflammatory induced BBB dysfunction and innovate therapies for modulating the severity of chronic inflammatory pain.