Hemophilia and other coagulation disorders: neurologic aspects
Jun. 20, 2022
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The blood-brain barrier is a dynamic conduit for transport between blood and brain of those nutrients, peptides, proteins, or immune cells that have access to certain transport systems localized within the blood-brain barrier membranes. Designed to protect the brain from harmful agents, it is also a barrier to CNS therapeutics. This article examines the anatomy and physiology of the blood-brain barrier as a basis for understanding neurologic disorders and for strategies to deliver therapeutics to the brain. Various transporter systems in the blood-brain barrier play an important role in the exchange of nutrients and can be utilized for drug delivery. Impaired blood-brain barrier in malignancies, trauma, and infections can be used to facilitate the passage of therapeutic agents. Methods for the assessment and modulation of the blood-brain barrier are also described.
• The blood-brain barrier is an important conduit of nutrients and cells from the blood to the brain.
• It also has an important function in protecting the brain from the entry of harmful substances.
• Knowledge of impairment of permeability of the blood-brain barrier in various neurologic disorders is important in understanding the pathomechanisms and devising strategies for management.
• Permeability of the blood-brain barrier is manipulated for drug delivery to the brain.
For over a century it has been recognized that the entry of certain substances into the brain is restricted. The old concept of the blood-brain barrier as a passive, impermeable barrier that segregates blood and brain interstitial fluid is giving way to the idea that the blood-brain barrier is a dynamic conduit for transport between blood and brain of those nutrients, peptides, proteins, or immune cells that have access to certain transport systems localized within the blood-brain barrier membranes. The historical evolution of knowledge concerning the blood-brain barrier is shown in Table 1.
Observation, concept, and comments
Aniline dyes injected intravenously were rapidly taken up by all the organs except the brain (19).
Coining of the term blood-brain barrier to describe the phenomenon (30).
Expansion of the original blood-brain barrier concept by the demonstration that intrathecal administration of trypan blue results in a generalized staining of the brain tissue, whereas intravenous application does not. Hypothesis put forward that the vehicle for substance transport was the CSF, which allegedly gained access to the brain via the choroid plexuses (20).
1921 to 1922
Intracerebral distribution of various substances was observed. "Barriére hémato-encephalique" was defined as a cerebral blood vessel compartment in which choroid plexus was semipermeable, facilitating the flow of substances from the blood into the CSF (46; 47).
Showed defects in the blood-brain barrier in brain diseases and demonstrated transient opening or disruption of the blood-brain barrier after intracarotid arterial administration of hypertonic solutions (08).
Electron microscopy showed a lack of extracellular fluid compartment in the gray matter, and this was given as an explanation of the failure of tracers to enter the brain. This was later shown to be an artifact in 1960s.
Further electron microscopy studies on "freeze-substituted" tissue demonstrated extracellular fluid in the cortex (52).
Tight junctions between brain endothelial cells is established as the location of the blood-brain barrier (42).
Blood-brain barrier permeability to hexoses, amino acids, and amines is demonstrated by radiolabeled substances (40).
Description of the "sink effect" gradient favoring the passage of substances in extracellular fluids from brain to CSF with the CSF constantly circulating and carrying substances away (15).
Studies in molecular biology of the blood-brain barrier. Cloning and sequencing of glucose transporter gene (53).
Other neural barriers are the blood-cerebrospinal fluid barrier, the blood-retinal barrier, the blood-labyrinth barrier, and the blood-nerve barrier, which is applicable only to the peripheral nervous system. The blood-brain barrier has been much more extensively investigated than the blood-nerve barrier. Several enzymes, transporters, and receptors have been investigated at both the blood-nerve barrier and blood-brain barrier, as well as in the perineurium of peripheral nerves, which is also a metabolically active diffusion barrier. A neurovascular unit, consisting of endothelial cells, neurons, and glia, regulates the blood-brain barrier. Knowledge of the blood-brain barrier is important in neurology for the following reasons:
• Understanding of brain function
An understanding of specific interactions between the brain endothelium, astrocytes, and neurons that may regulate blood-brain barrier function and how these interactions are disturbed in pathological conditions could lead to the development of neuroprotective and restorative therapies.
• Blood-brain barrier is an anatomical barrier for protection of the brain from blood milieu
Anatomical as well as physiological barrier. The aim of this barrier is to protect the brain from substances in the blood. The structural basis of the blood-brain barrier is the presence of "tight" junctions between endothelial cells lining the brain capillaries in contrast to the peripheral tissue capillaries that have interendothelial cleft passages. Several physiologic properties make the endothelium in the central nervous system distinct from the vasculature found in the periphery. Anatomically, blood-brain barrier-tight junctions are more like epithelial-tight junctions than to endothelial-tight junctions in peripheral blood vessels. The development of tight junctions depends on two primary processes: (1) the appearance of high levels of the tight junction protein “occludens” and (2) intracellular signaling processes that control the state of phosphorylation of junctional proteins.
Fenestrations found in capillaries of other organs are absent in the brain and many capillaries are "seamless." The formation of barrier-type capillaries is induced by signals from adjacent astrocytes. If capillary integrity is compromised, a pericyte located on the wall of the capillary exercises the barrier function. The pericytes are phagocytic microglial cells that are responsible for maintenance of homeostasis between the blood and the brain.
The anatomical barrier is not complete. Some regions of the brain, eg, the circumventricular organs that include the area postrema, the neural pituitary gland, the median eminence, the pineal gland, and the organum vasculosum of the lamina terminalis have nonblood-brain barrier or "leaky" capillaries like those in the choroid plexus.
Biochemical barrier. This barrier is constituted by certain enzymes in the brain capillary endothelial cells. Most neurotransmitters have low blood-brain barrier permeability, which allows separation of the peripheral from the central pool of neurotransmitters.
Monoamine oxidases can metabolize plasma-borne biogenic amines so that the brain is protected from systemic bursts of epinephrine. Aminopeptidases degrade plasma-borne enkephalins. However, amino acid transporters permit significant quantities of levodopa prodrug to penetrate the blood-brain barrier, and metabolized dopamine is delivered to the brain this way to treat patients with Parkinson disease.
Regulatory functions. The term “regulatory functions” collectively describes all processes by which the unique functions of the brain are maintained. There are distinct differences in the blood-brain barrier regulation of nutrients in different parts of the brain and varying degrees of activity of the brain. For example, blood-brain barrier glucose transporter is a functional participant in the cerebral glucose homeostasis. The endothelia also regulate blood-to-brain passage of nutrients and peptides as well as brain-to-blood movement of acidic compounds.
The brain needs all the vitamins, excepting K and D. Most of the vitamins can cross the blood-brain barrier by different carrier systems. The transport processes have a regulatory role as follows:
• Saturation of a carrier-mediated transport limits entry of vitamins into the brain when the blood concentration is abnormally high.
• Slowness of vitamin transport across the blood-brain barrier prevents a sudden loss of brain vitamin content in case of deficiency states. Losses of vitamins are also limited by the binding of vitamins to coenzymes.
The blood-brain barrier, by selectively transporting some peptides and regulatory proteins in the blood-to-brain or the brain-to-blood direction, regulates communications between the CNS and gastrointestinal tract.
Other neural barriers. There are some similarities, as well as structural and functional differences, between blood-brain and other neural barriers.
Blood-cerebrospinal fluid barrier. The blood-cerebrospinal fluid barrier is formed by the choroid plexus, and the tight junction between the epithelial cells is involved in the functional role of this barrier. Some studies also suggest the presence of a transport system on both the blood-brain barrier and blood-cerebrospinal fluid barrier that is responsible for ligand efflux from the central nervous system into the blood. Together with the anatomical features, this transport system also has a functional significance in preventing the entry of several ligands into the central nervous system. In addition to such an efflux mechanism, both the blood-brain barrier and blood-cerebrospinal fluid barrier have functional roles in transporting micronutrients into the central nervous system from the blood by either a carrier- or receptor-mediated mechanism. The choroid plexus is smaller in size than the total surface area of the cerebral capillaries. However, the microvilli and numerous folds of the epithelium increase the surface area available for exchanges. It provides some pharmacotherapeutic opportunities that are not available via the blood-brain barrier. Cerebrospinal fluid may also act as a "third circulation," conveying substances secreted into it rapidly to many brain regions.
Blood-nerve barrier. In peripheral nerves, the endothelial lining of the vasa nervosum is formed by continuous, nonfenestrated endothelial cells with tight junctions, and this formation renders it impermeable to macromolecules in the circulation. The perineurium is not protected, but innermost layers of the perineural sheath isolate the interstitium in the same way as the brain is isolated by the blood-brain barrier. This barrier may be deficient at the posterior root ganglia.
Blood-retinal barrier. The blood-retinal barrier is formed by the retinal vascular endothelium in conjunction with tight junctions of the retinal pigment epithelium. The inner and the outer limiting membranes of retina are relative diffusion barriers; they may retain fluid and electrolytes that leak through blood-retinal barrier, leading to retinal edema. This may occur in retinal vascular and inflammatory diseases.
Blood-labyrinth barrier. The blood-labyrinth barrier is characterized by tight junctions lining blood vessels in the labyrinth. This regulates the transport of various substances in and out of the fluid-containing parts of the inner ear. The ability to manipulate this barrier would be useful in managing ototoxicity of some systemically administered agents, such as antibiotics and antineoplastic agents.
Passage of substances across the blood-brain barrier. Several carrier or transport systems, enzymes, and receptors that control the penetration of molecules have been identified in the blood-brain barrier endothelium by physiological and biochemical studies. These are shown in Table 2.
Transporters or system
• Glucose transporter GLUT 1
• D-glucose, dehydroascorbic acid
Amino acid transporters
• Excitatory amino acids EAAT 1,2,3
• Aspartate, glutamate
Organic anions and cation transporters
• P-aminohippuric acid
ABC adenosine triphosphate-binding cassette) transporters
• Vincristine, cyclosporin A
• P-glycoprotein efflux system
Miscellaneous transporters and receptors
• Adenosine receptor
ABC transporters. These function at the blood-brain barrier as ATP-driven xenobiotic efflux pumps and limit delivery of small molecule drugs to the brain (36). When ABC transporters limit neurotoxicant entry into the CNS, they are neuroprotective; but when they limit therapeutic drug entry, they are obstacles to drug delivery to treat CNS diseases. Understanding the regulation of expression and transport activity of these transporters might help in improving drug delivery to the brain.
P-glycoprotein (P-gp) is the most investigated ABC (efflux) transporter. Apart from its role as an efflux pump for drugs such as vinblastine, it is also implicated in neurodegenerative diseases such as Alzheimer disease. Altered function of P-gp can be studied in vivo using PET, but no suitable radiopharmaceutical is yet available for this purpose (41).
A2A adenosine receptor (AR). Results of experimental studies suggest that AR signaling is an endogenous modulator of blood-brain barrier permeability. Regadenoson, an FDA-approved A2A AR agonist used as a cardiac nuclear stress test, also increases blood-brain barrier permeability and facilitates CNS entry of macromolecules like dextrans. Thus, A2A AR modulation on blood-brain barrier endothelial cells can be fine-tuned for drug delivery to the brain (27).
Glucose transporter. This provides the major source of energy for the brain, ie, glucose. More than 98% of the energy supply generated in the brain to sustain neuronal function arises from combustion of blood-borne glucose. The rate of glucose transport depends on the glucose concentration of the blood and increases until saturation is reached. The transport rate across the endothelial membrane is essentially identical in both directions.
Under normal conditions, blood-brain barrier glucose transport proceeds at rates approximately 2-fold greater than the existing glucose phosphorylation and utilization rates. However, when plasma glucose falls to hypoglycemic levels, glucose transport through the blood-brain barrier falls to levels that become limiting for glucose utilization. Glucose utilization rates are increased in the convulsing brain, but glucose utilization may be limited by blood-brain barrier glucose transport. Studies of blood-brain barrier glucose permeability and regional brain glucose metabolism show that no major adaptational changes occur in the maximal transport velocity or affinity to the blood-brain barrier glucose transporter during hyperglycemia.
Creatine transporter. The blood-brain barrier supplies creatine to the brain for an energy-storing system, and creatine transporter localized at the brain capillary endothelial cells is involved in blood-brain barrier creatine transport.
Amino acid transporters. Certain small amino acids are synthesized in the brain and act as inhibitory neurotransmitters, eg, gamma-aminobutyric acid. For this reason, their concentration in the brain needs to be controlled constantly. A carrier system exists for this purpose and transports small amino acids out of the extracellular space of the brain along with sodium ions according to the ion gradient. The amino acids are then delivered to the blood circulation by transport systems localized in the luminal endothelial membrane.
Gamma-glutamyl transpeptidase catalyzes amino acid transfer in membranes of various organs and has been localized in brain capillaries where it serves as a part of the amino acid transport system of the brain. Cerebrovascular gamma-glutamyl transpeptidase protects the blood-brain barrier against the barrier-disturbing effects of leukotriene C4 by breaking it down before it can reach its receptors on the endothelial surface.
Glutamate flux from plasma into the brain is mediated by a transport system at the blood-brain barrier. Glutamate concentration in brain interstitial fluid is only a fraction of that of plasma and is maintained independent of small fluctuations in plasma concentration. Blood-brain barrier is a single component of a regulatory system that helps maintain brain interstitial fluid glutamate concentration independently of the circulation.
Ionic transporter. The concentration of the sodium and potassium ions in the brain is controlled by sodium-potassium ATPase, which is localized in the endothelial cell membrane of the brain capillaries. The ionic pump allows upstream movement of sodium against the concentration gradient from the endothelial cytoplasm into the brain compartment and potassium movement in the reverse direction. The blood-brain barrier provides a fluid environment with low potassium content to achieve nerve conduction. An increase in blood-brain barrier mitochondria and electrical resistance along with Na+-K+ ATPase contribute to the maintenance of low potassium levels.
Organic anion transporter 1. This is a multispecific transporter that accepts small, organic anions such as p-aminohippurate. Organic anion transporter 1 is expected to be responsible for the uptake of the p-aminohippurate from the brain to the brain capillary endothelial cells.
Blood-brain barrier-specific enzymes. Enzymes that control the penetration of molecules across the blood-brain barrier are the following:
• 1-naphthol UDP-glucuronyltransferase (p-nitrophenol)
An example of the mode of action of enzymes is monoamine oxidase, which provides an enzymatic barrier and hinders the influx of monoamine precursors into the brain. After their entry into the endothelial cells, monoamines are decarboxylated by cytoplasmic monoamine oxidase, thus, effectively preventing a flood of peripheral monoaminergic neurotransmitters in the neuronal environments.
Receptor-mediated peptide and protein transcytosis. The transport of peptides and proteins across cellular barriers, transcytosis, has been documented in several parts of the human body. Examples include the transport of IgG across the intestinal epithelium and human placenta, the transport of insulin and insulin-like growth factors across the aortic endothelium, and the transport of epidermal growth factor across the kidney epithelium. It is not surprising that transcytosis occurs across the blood-brain barrier. In addition to the unidirectional and bidirectional transport of small molecules, other macromolecules can enter the brain tissue from the blood by a receptor-mediated process. An example of this is the transport of transferrin across the blood-brain barrier. Brain cells require a constant supply of iron to maintain their function and brain may substitute its iron through transcytosis of iron-loaded transferrin across the brain microvasculature. Other biologically active proteins such as insulin and immunoglobulin G are actively transcytosed through blood-brain barrier endothelia. The presence of receptors involved in the transcytosis of ligands from the blood to the brain offers opportunities for developing new approaches to the delivery of therapeutic compounds across the blood-brain barrier.
Molecular biology of the blood-brain barrier. The molecular composition of the blood-brain barrier has been studied by immunocytochemistry, and the results of these studies show that the blood-brain barrier exhibits a specific collection of structural and metabolic properties that are also found in the tight-transporting epithelia. These conclusions are substantiated by antibodies that recognize proteins of nonblood-brain barrier origin and blood-brain barrier-specific proteins. Blood-brain barrier-specific immunoprobes have a potential application for investigating the pathomechanisms that lead to the breakdown of blood-brain barrier. Different patterns of blood-brain barrier disintegration are anticipated under different pathological conditions, eg, inflammatory reactions versus tumors.
Genes that are selectively expressed at the blood-brain barrier have been cloned. These include GLUT-1 (glucose transporter) and GGTP (gamma-glutamyl transpeptidase). The blood-brain barrier GLUT-1 transporter maintains the availability in the brain of glucose and the regulation of the protein is mediated at the levels of the gene transcription, mRNA translation and stability, and posttranscriptional processes. GLUT-1 plays a role in the development of the cerebral endothelial cells with blood-brain barrier properties in vivo. Knockdown of GLUT-1 in an animal model was shown to produce loss of the cerebral endothelial cells and downregulation of the junctional proteins important for intactness of the tight junctions with resulting leaky blood-brain barrier and vasogenic cerebral edema (55). This finding suggests that research into modulation of GLUT-1 expression may lead to therapeutic strategies for preventing vasogenic cerebral edema.
Molecular mechanisms of the "tight junctions" of the blood-brain barrier are just being unraveled. In addition to occludens, other molecules (such as claudins) may be responsible for the integrity of the tight junctions. A molecular analysis of the blood-brain barrier has clinical relevance for the development of new therapeutic strategies for neurologic disorders.
In vitro studies of blood-brain barrier in models. Most in vitro models of blood-brain barrier use nonhuman, monolayer cultures for therapeutic-delivery studies, relying on transendothelial electrical resistance measurements without other tight-junction formation parameters. An in vitro 3-dimensional (3D) model incorporating relevant human, in vivo cell types and basal lamina proteins has been constructed with human brain endothelial cells, human astrocytes, and human brain pericytes in mono-, co-, and tricultures (34). This is the first real, 3D, all-human blood-brain barrier model, and it is unique for detecting cancer metastases from the breast or lung to the brain. It will also be a perfect medium for testing nanoparticle delivery of drugs and to attempt to create temporary openings in the barrier that will let medications pass into the brain. It will also shorten the time it takes to test a new drug and to take it into clinical trials.
Control of permeability of blood-brain barrier. Several signaling factors can control blood-brain barrier permeability by regulating the structural components (02). These include inflammatory mediators, free radicals, vascular endothelial growth factor, matrix metalloproteinases, and microRNAs.
Choroid plexus and the blood-cerebrospinal fluid barrier in disease. Integrity of the choroid plexus is critical for maintaining brain homeostasis and blood-CSF barrier permeability. The choroid plexus is involved in penetration of various pathogens into the CNS as well as the development of neurodegenerative and autoimmune diseases (45). Moreover, the choroid plexus was shown to be important for restoring brain homeostasis following stroke and trauma.
Blood-brain barrier in neurologic disorders. Genomic and proteomic analyses have been used to study the blood-brain barrier and how it relates to the pathogenesis of major neurologic diseases. Shear stress associated with blood flow in arteries has variable effects on endothelial cells, which are modulated by induction or suppression of genes regulating endothelial physiology, eg, formation of inter-endothelial tight junction and expression of specific carrier-mediated transporters (14). These findings can form the basis of developing innovative therapeutic strategies to improve the management of blood-brain barrier-related diseases.
Disorders of the brain that involve the blood-brain barrier are shown in Table 3. Some of the mechanisms that underlie these disorders are:
Inflammation. In general, immune cell invasion across the blood-brain barrier is highly restricted and carefully regulated. An invasion of activated white blood cells can create a proinflammatory local environment in the CNS, leading to immune-mediated diseases of the nervous tissue. Brain inflammation can both cause and result from blood-brain barrier dysfunction (28). Loss of blood-brain barrier integrity allows immune cells, inflammatory molecules, and albumin to infiltrate, leading to glial activation and disturbance of the extracellular milieu around neurons in the neurovascular unit. Blood-brain barrier disruption and neuroinflammation are pathophysiological mechanisms of the diffuse manifestations of neuropsychiatric systemic lupus erythematosus (18).
Several studies show that hypoxia or inflammatory pain increase permeability of the blood-brain barrier, induce changes in the expression of tight junction proteins, and affect drug uptake into the central nervous system (33). This information may be taken into consideration for the treatment of disorders with an inflammatory component and for improving delivery of drugs across the blood-brain barrier.
Cerebral edema. Vasogenic edema can occur following blood-brain barrier disruption. Water, ions, and plasma proteins cross the blood-brain barrier toward the interstitium if the driving forces for the flow are excessive and if the blood-brain barrier permeability is enhanced.
Cytokines. Cytokines circulating in the blood can be transported across the blood-brain barrier with increased permeability and can directly affect CNS functions; this may be physiological as well as pathological.
Blood-brain barrier permeability is increased in other pathological conditions, such as infections and tumors, and facilitates the entry of chemotherapeutic agents into the lesions. This barrier can also be opened pharmacologically or osmotically. Injuries, infections, and tumors are well known to disrupt the blood-brain barrier.
Stress. Stress has been shown to increase the permeability of the blood-brain barrier. Stress is accompanied by elevation of proinflammatory mediators such as serum cortisol, IL-6, and TNF-alpha as well as increase in S100B, a biomarker of increased permeability of the blood-brain barrier (31).
Chronic sleep loss. Sleep loss induces a systemic low-grade inflammation with release of several molecules, such as cytokines, chemokines, and acute-phase proteins, which may induce changes in cellular components of the blood-brain barrier, particularly the brain endothelial cells. A hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption emphasizes the regulatory effect of inflammatory molecules on tight junction proteins (24).
Neurodegenerative disorders. Impairment of cerebral blood flow and blood-brain barrier dysfunction are early findings in neurodegenerative disorders (48). Disruption of the blood-brain barrier in neurodegenerative disorders may initiate or contribute to a "vicious circle" of the disease process, resulting in progressive synaptic and neuronal dysfunction. Aging of the cerebral microcirculation results in significant alteration in the blood-brain barrier. Aging humans have altered blood-brain barrier function of select carrier-mediated transport systems, including the transport of choline, glucose, butyrate, and triiodothyronine. Accumulating evidence suggests that increased permeability of the blood-brain barrier to blood-borne proteins is favorable for the development of neuropathologic changes and the formation of amyloid plaques in the brain in Alzheimer disease.
A defective blood-brain barrier may be present in Alzheimer disease; this would allow circulating amyloid beta to enter the brain. Biopsy specimens obtained during neurosurgical procedures (tumors and dementia) show that only those microvascular segments directly surrounded by amyloid plaques or representing amyloid angiopathy show increased permeability to endogenous albumin, and numerous immunosignals over the amyloid deposits in plaques and in the wall of angiopathic vessels suggest the affinity of extravasated albumin to the amyloid material. The expression of low-density lipoprotein receptor-related protein-1, a key amyloid beta clearance receptor at the blood-brain barrier, is suppressed early in Alzheimer disease and may influence amyloid beta clearance across the blood-brain barrier (06). A study on early Alzheimer disease patients using dynamic contrast material–enhanced MRI has shown increasing leakage in the deep gray matter and cortex that is associated with cognitive decline (51). MRI can also detect brain microbleeds, which is another indication of leakage across the blood-brain barrier. Persons with early cognitive dysfunction develop brain capillary damage and breakdown of blood-brain barrier in the hippocampus regardless of amyloid beta and/or tau biomarker changes in Alzheimer disease indicating that blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction independent of amyloid beta and tau (38).
The age-dependent blood-brain barrier breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsens with mild cognitive impairment and its progression to Alzheimer disease, which correlates with injury to blood-brain barrier-associated pericytes, as shown by the CSF analysis (37).
Significantly increased permeability of the blood-brain barrier in the postcommissural putamen of Parkinson disease patients has been shown by use of histologic markers of serum protein, iron, and erythrocyte extravasation (21). The dense innervation of the striatum by regions affected in Parkinson disease enables exploitation of this permeability for therapeutic purposes.
Alexander disease is caused by mutations in the GFAP gene leading to intracellular accumulation of glial fibrillary acidic protein resulting in death of astrocytes. Neurodegeneration in Alexander disease is accompanied by disruption of blood-brain barrier.
Mitochondrial encephalopathies. Study of the blood-cerebrospinal fluid and blood-brain barriers by in situ hybridization and immunohistochemistry techniques in models of mitochondrial encephalopathies has revealed alterations that are relevant to the pathogenesis of central nervous system dysfunction in these disorders. Manipulation of the functions of these barriers may provide opportunities for therapeutic intervention.
Multiple sclerosis. Contrast-enhanced MRI in patients with multiple sclerosis show that increased permeability of the blood-brain barrier commonly occurs with this disease. Lymphocyte recruitment into the brain across endothelial cells of the blood-brain barrier, which is otherwise restricted and well regulated, represents a critical event in pathogenesis of multiple sclerosis (13). The changes in capillary permeability often precede T2-weighted MRI evidence of tissue damage. Increased gelatinase B (a type of matrix metalloproteinase) is associated with an open blood-brain barrier on MRI. Steroids may improve capillary function by reducing activity of gelatinase B.
Various inflammatory factors produced by perivascular cells in multiple sclerosis affect the permeability of the blood-brain barrier. One of these, the intercellular adhesion molecule-1, binds to its leukocyte ligands and allows activated leukocytes entry into the central nervous system. Pathological reflux of venous flow in the cerebral and spinal veins increases the expression of intercellular adhesion molecule-1 by the cerebrovascular endothelium, which, in turn, could lead to increased permeability of the blood-brain barrier.
Enhance expression of vascular endothelial growth factor A (VEGF-A) acting via endothelial nitric oxide synthase (eNOS) has been implicated in breakdown of blood-brain barrier in multiple sclerosis. Inactivation of astrocytic VEGF-A expression has been shown to reduce blood-brain barrier breakdown and decrease lymphocyte infiltration and demyelinating lesions as well as reduce paralysis in a mouse model of multiple sclerosis (04). Systemic administration of a selective eNOS inhibitor in mice abrogated VEGF-A-induced blood-brain barrier disruption and protected against neurologic deficit in this multiple sclerosis model system. Blocking the VEGF-A pathway by various strategies might be effective in preventing CNS entry of extrathecally produced autoantibodies in demyelinating diseases.
Central nervous system injuries. Blood-brain barrier is disrupted in acute severe traumatic brain injury. The high glucose transporter Glut1 density observed in capillaries from acutely injured brain occurs concomitantly with compromised blood-brain barrier function. Vascular endothelial growth factor appears to be increased in brain tissue during cerebral trauma, and it also increases the permeability of the blood-brain barrier via the synthesis and release of nitric oxide. Concentrations of serum biomarker S100B accurately indicate blood-brain barrier dysfunction at 12 h after traumatic brain injury (07). The blood-CSF barrier has a role in posttraumatic recruitment of inflammatory leucocytes, such as monocytes into the brain, which has a detrimental effect on neuronal survival and functional recovery (49).
Traumatic brain injury (TBI) is a risk factor for dementia, and neurodegenerative changes have been described in late survivors. Multiple brain regions were examined using immunohistochemistry for the blood-brain barrier biomarkers, integrity fibrinogen and immunoglobulin G, with widespread disruption of the barrier persisting in a high proportion of late survivors, which may be a link to dementia (22).
Epilepsy. Transient changes, correlated with the site of the epileptogenic focus but not representing an underlying lesion, are shown on MRI and are presumably due to a temporary alteration of the blood-brain barrier. Transient blood-brain opening that occurs during epileptic seizures may upregulate the expression of P glycoprotein and other drug efflux transporters that contribute to drug resistance in epilepsy. It is generally accepted that blood-brain barrier failure due to central nervous system diseases may produce seizures. However, blood-brain barrier failure may be a factor contributing to the development of seizures in the absence of underlying disease. Experimental studies in animals support the involvement of glia-derived brain inflammation and blood-brain barrier damage in epileptogenesis (32).
Cerebrovascular disease. Several vascular diseases affecting the brain impair blood-brain barrier. These include stroke, cerebral arteriovenous malformations, Moyamoya syndrome, small vessel diseases of the brain causing leukoencephalopathy, cerebral amyloid angiopathies, cerebral cavernomas, and ruptured intracranial aneurysms.
Cerebral ischemia in experimental animals has been shown to be associated with increased permeability of the blood-brain barrier. Cytokines, such as tumor necrosis factor alpha, are involved in this process. Decrease of nutrients may lead to endothelial membrane failure. Ischemia may also compromise the blood-brain barrier by increasing vesicular transport across it and by opening tight junctions. Degree of ischemia may determine the size of the openings in the barrier. In mild ischemia, only small molecules may penetrate whereas in severe ischemia, large molecules can also cross the blood-brain barrier. Increased blood-brain barrier permeability in ischemic stroke contributes to cerebral vasogenic edema, hemorrhagic transformation, and increased mortality. Regulation of the permeability of blood-brain barrier in response to cerebral ischemia by integration of sirtuin1 (Sirt1) and sirtuin3 (Sirt3), two well-characterized members of the silent information regulator 2 (Sir2) family of proteins, has been tested in an in vitro model (12). Results show that Sirt1-Sirt3 axis may act as an important modulator in blood-brain barrier physiology and could be a therapeutic target for ischemic stroke by regulating generation of reactive oxygen species via mitochondria.
A delayed contrast extravasation MRI-based method enabled detection of blood-brain barrier disruption in 27% of the stroke patients who did not have abnormalities on conventional contrast-enhanced MRI (25). This may help predict the likelihood of developing cerebral edema and hemorrhagic complications following reperfusion in stroke patients. A reliable method of estimating blood-brain barrier permeability following acute stroke is based on first-pass perfusion CT data (39).
Using CT perfusion during the first 3 months following stroke, disturbances of blood-brain barrier as well as cerebral perfusion have been shown in the noninfarcted basal ganglia and thalamus of patients with lacunar/subcortical stroke (54). Possible relationship of these disturbances to chronic cognitive impairment needs further study.
Blood-brain barrier breakdown is a mechanism underlying cerebral hyperperfusion syndrome that occurs as a complication of surgery for carotid stenosis (26). Increased permeability of the membrane allows albumin extravasation and cerebral edema leading to seizures. Extent of blood-brain barrier breakdown in hyperacute stroke, as indicated by the biomarker matrix metalloproteinase-9 in CSF and blood relates to initial stroke severity and secondary brain damage (09).
Infections. Pathogens target both the blood-brain barrier endothelium (causing encephalitis) and the choroid plexus epithelium (leading to meningitis). Routes of entry are diverse, including paracellular and transcellular penetration. Bacteria enter the central nervous system following a direct interaction with the luminal side of the cerebral endothelium. Because only a limited number of pathogens can cross these tight barriers and invading the meninges, specific properties are required. Circulating microbial products can induce a loss of blood-brain barrier function. In the case of pneumococcal infections, bacteria bind to the endothelial cell surface via platelet-activating factor receptors. Spread of infection to the CNS induces increased vesicular transport across cells and separation of tight junctions of the blood-brain barrier, leading to the release of inflammatory peptides such as interleukin-1, tumor necrosis factor, and metalloproteinases. Impairment of the blood-brain barrier by infection may facilitate the influx of antibiotics. Reduction of inflammation of the meninges by corticosteroids with resulting reduction in the leakiness of the blood-brain barrier might reduce this influx.
Cryptococcus neoformans tends to invade the brain, and it crosses the blood-brain barrier by using membrane rearrangements, intracellular signaling pathways, and cytoskeletal activations (50). Several cryptococcal genes related to the passage through blood-brain barrier have been identified, and Cryptococcus-derived microvesicles may contribute to cryptococcal brain invasion.
Changes in blood-brain barrier structure and function correlate with the signs and symptoms observed in children with cerebral malaria. Binding of parasitized erythrocytes to cerebral endothelium plays a key role in disease pathogenesis. Metabolic acidosis induced by intraerythrocytic stages of Plasmodium falciparum, which in turn correlates with apoptosis of parasitized erythrocytes, increases blood-brain barrier permeability (56).
Viruses that enter the CNS by indirect routes such as olfactory and spinal nerves may not significantly impair the blood-brain barrier, and the entry of antibiotics in the CNS is not facilitated. HIV usually enters the brain via infected monocytes, which traverse abnormal tight junctions of the blood-brain barrier or penetrate endothelial cells. After entry, HIV can proliferate in the microglia and is released into the venous blood via the arachnoid granulations while it is protected from systemically administered antiviral drugs by the blood-brain barrier. Available evidence also suggests that microbial proteins are the major genetic determinants mediating penetration across the blood-brain barrier. Viral proteins and cytokines can enter the central nervous system from the blood and provide a mechanism by which HIV-1 can affect central nervous system function independent of viral transport. Blood-brain barrier damage is prevalent in HIV-positive patients and may enhance cell trafficking to the central nervous system with main determinants being advanced immune depression as well as compartmental viral replication (10). Mechanisms of blood-brain barrier disruption by neurotropic viruses include alterations in expression or phosphorylation of tight junction proteins, disruption of the basal lamina, and disruption of the actin cytoskeleton (01). In the absence of such mechanisms, indirect effects of viruses on the immune system are likely causes of barrier disruption.
Immunofluorescent images of B cells have shown that JC virus infects these cells and uses them as a vehicle for transmigration across the blood-brain barrier to transmit infection to naive glial cells in the brain (11).
Fungal and parasitic pathogens may penetrate the blood-brain barrier by similar mechanisms. Understanding the fundamental mechanisms of microbial penetration of the blood-brain barrier may help develop novel approaches to prevent the mortality and morbidity associated with central nervous system infectious diseases.
Autoimmune disorders. In some autoimmune neurologic diseases, such as Guillain-Barré syndrome, demyelinating polyneuropathy, and motoneuron disease, persistent immunological attack of microvascular endothelial cells by glycolipid-directed autoantibodies may lead to extensive cellular damages, resulting in increased permeability across the brain-nerve barrier, the blood-brain barrier, or both.
Brain tumors. Although primary brain tumors are associated with secondary disruption of the blood-brain barrier, dysfunction of the barrier during development may be associated with tumor formation. Structural and functional abnormalities of the vascular microenvironment determine pathophysiological characteristics of gliomas, such as loss of blood-brain barrier function, tumor cell invasiveness, or permeability to chemotherapeutic agents. Blood-brain barrier is impaired in malignant brain tumors such as glioblastoma multiforme. Endothelial-tight junctions are defective in malignant gliomas resulting in cerebral edema and contrast enhancement on neuroradiological examination. The mechanisms underlying blood-brain barrier breakdown are not well understood. Because non-neoplastic astrocytes are required to induce blood-brain barrier features of cerebral endothelial cells, it is possible that malignant astrocytes have lost this ability due to dedifferentiation.
The degree of impairment of the blood-brain barrier varies, being more marked in the necrotic center and less at the periphery of the tumor. These variations may result in reduction of concentrations of chemotherapeutic agents at the rapidly growing periphery and can contribute to failure of chemotherapy.
Blood-brain barrier usually resists the passage of circulating tumor cell from another organ to prevent metastases in the brain. Cancer metastases can go to various organs such as the lungs, liver, and brain. A study has shown that an exosomal signature of a cancer could be used to predict the organ to which it may metastasize, eg, brain-tropic exosomes contain abundant ITGb3 integrins that have propensity for forming brain metastasis as they are taken up by brain endothelial cells and produce vascular leakiness in the intact blood-brain barrier (23). A study has demonstrated the ability of kinin peptide B1R and B2R agonist analogs to improve blood-brain barrier penetration of the chemotherapeutic agent doxorubicin (DOX) in rats with moderately developed glioblastoma (44). The idea of using mono or dual B1R/B2R agonist approach could further improve the extent of drug delivery beyond the blood-brain barrier, as supported by data presented herein, and this would enable an increased delivery compared to a single intra-arterial administration of carboplatin (or other suitable chemotherapeutics), without requiring the heavy setup needed for hyperosmolar blood-brain barrier disruption maneuvers, including general anesthesia.
Factors that increase the permeability of the blood-brain barrier. Various chemical and pharmacological factors that increase the permeability of the blood-brain barrier are shown in Table 4. Knowledge of these factors is important for devising strategies for manipulation of this barrier.
• Alpha-adrenergic agonists
• Operations involving penetration of the brain tissues
Drug abuse-induced blood-brain barrier dysfunction. Use of psychostimulants can disrupt blood-brain barrier integrity/function, leading to an increased risk of neurovascular complications, which are attributed to oxidative stress (43). Synergistic pathological impact of psychostimulants and HIV infection on blood-brain barrier integrity further points to the unifying role of endothelial oxidative stress.
Blood-brain barrier and bilirubin encephalopathy. The pathogenesis of bilirubin encephalopathy is multifactorial, but it involves the transport of bilirubin across the blood-brain barrier and delivery to target neurons to cause kernicterus. This encephalopathy occurs mostly in newborns with severe unconjugated hyperbilirubinemia. The blood-brain barrier is intact in full-term newborns, but an immature barrier in premature infants might be a risk factor for kernicterus. Although it is known that the disruption of the blood-brain barrier facilitates bilirubin transport into the brain, its role in the causation of kernicterus is uncertain.
Effects of electromagnetic field on the blood-brain barrier. This is controversial because in some studies exposure to electromagnetic fields at nonthermal levels disrupts the blood-brain barrier, whereas others do not show any effects on this barrier.
Alteration in permeability of blood-brain barrier as an adverse effect of drugs. Psychoactive drugs such as methamphetamine and cocaine can alter the permeability of the blood-brain barrier, which, in turn, can further contribute to their neurotoxicity (17).
Blood-brain barrier disruption after endovascular therapy. Disruption of blood-brain barrier has been reported in 58.2% of patients following endovascular procedures and has a detrimental effect on their outcome (16).
• Clinical applications are mainly focused on the assessment of the integrity of the blood-brain barrier.
• Manipulation of the blood-brain barrier is an aid to drug delivery to the brain.
Clinical assessment of the blood-brain barrier. Two main approaches are used for studying the integrity of human blood-brain barrier in vivo: (1) structural imaging employs contrast agents that only penetrate the blood-brain barrier at sites of damage, and (2) functional imaging is used to study the transport of substances across the blood-brain barrier- both intact and damaged. Structural imaging employs contrast agents with CT scanning and is relatively insensitive. MRI with the contrast agent gadolinium is more sensitive. Hyperintense acute reperfusion injury marker (HARM) is gadolinium enhancement of cerebrospinal fluid on fluid-attenuated inversion recovery MRI and may be a useful imaging biomarker to evaluate matrix metalloproteinase-9, which may play a role in blood-brain barrier disruption after ischemic stroke (05).
Functional imaging is done with PET and can quantitate cerebral uptake of therapeutic agents, such as cytotoxic agents and monoclonal antibodies. SPECT is less versatile than PET but can provide semiquantitative measurement of blood-brain barrier leakage of albumin or red blood cells. PET could be a useful in vivo tool for examination of the role of the blood-brain barrier in the pathophysiology of neurodegenerative and affective disorders.
Opening the blood-brain barrier facilitates the entry of superparamagnetic iron oxide conjugates used as adjuncts to MRI for diagnosis of brain metastases.
Therapeutic applications of blood-brain barrier manipulations. Manipulations of the barrier for therapeutic purposes are usually for two reasons: (1) to increase the permeability of the barrier to facilitate drug delivery to the brain and (2) to decrease the permeability of the barrier for treatment of diseases that result in detrimental increased permeability of the blood-brain barrier.
Manipulations for facilitating drug delivery to the brain. Several strategies that have been used for manipulating the blood-brain barrier for drug delivery to the brain are osmotic opening of the blood-brain barrier, chemical opening of the blood-brain barrier, neurostimulation, and the use of transport as well as carrier systems. The two that have been employed therapeutically are hypertonic solutions and lobradimil (a bradykinin analog).
Neurostimulation has been used to produce an indirect effect, ie, opening the blood-brain barrier in order to facilitate drug delivery to the brain. One device, Vascular Enabled Integrated Nanosecond (VEIN) pulse, involves insertion of minimally invasive electrodes into diseased brain tissue and application of multiple bursts of nanosecond pulses with alternating polarity that disrupt tight junction proteins responsible for maintaining the integrity of the blood-brain barrier without causing damage to the surrounding tissue (03). The plan is to use this technique in conscious patients under sedation; the technique could be combined with brain biopsy.
Other strategies for drug delivery to the brain involve bypassing the blood-brain barrier. Potential therapeutic applications of manipulation of the blood-brain barrier are mostly in use to facilitate drug delivery to brain tumors in clinical trials (see Drug delivery to the central nervous system). Examples of these strategies are the following:
• To facilitate the entry of anticancer agents into brain tumors
Methods of focal delivery of therapeutic and diagnostic substances to the brain across the blood-brain barrier are in experimental stages for infectious, genetic, neoplastic, and neurodegenerative disorders. An advantage will be the delivery of the genes to the required site as opposed to the exposure of the whole brain to the therapeutic agent. Genetic and other defects leading to brain changes in Down syndrome, Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, Gaucher disease, hypertension, and other disorders are rapidly being identified. Several effective therapeutic agents are available, but their use is limited pending improvement of drug delivery across the blood-brain barrier. In silico methods are available to predict blood-brain barrier penetration by drugs (29).
Decreasing the increased permeability of the blood-brain barrier due to disease. Neurotrophic factors (particularly the brain-derived neurotrophic factor and insulin-like growth factor type 1), when applied to the traumatized spinal cord in experimental animals, reduce the permeability of the blood-spinal cord barrier. These results suggest a possible beneficial effect of these factors in the treatment of spinal cord injury. Serine protease inhibitors reduce the increased blood-brain permeability induced by tumor necrosis factor alpha and may be useful for ameliorating vasogenic brain edema. Type IV phosphodiesterase inhibitors ameliorate experimental autoimmune encephalomyelitis by reducing cerebrovascular endothelial permeability, thus, diminishing tissue edema as well as entry of inflammatory cells and factors.
Regular physical exercise diminishes blood-brain barrier permeability by reinforcing antioxidative capacity and reducing oxidative stress and anti-inflammatory effects, which improve endothelial function and may increase the density of brain capillaries (35). Physical training programs may be useful as preventive measures for minimizing the risk of the onset of neuroinflammatory diseases. However, despite a sound theoretical background, it is uncertain if exercise training is effective in modulating permeability of the blood-brain barrier in specific neurologic disorders and needs to be investigated further.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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