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- Volume 15, Issue 9, 2016
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 15, Issue 9, 2016
Volume 15, Issue 9, 2016
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Tight Junctions of the Blood-Brain Barrier – A Molecular Gatekeeper
Authors: Hannelore Bauer and Andreas TrawegerA tight regulation of the neuroparenchymal microenvironment is imperative for proper neurological function. The flux of blood-borne ions and solutes is restricted by specialized tissue barriers and of the three main central nervous system barriers, the brain endothelium constituting the blood-brain barrier represents the major interface between blood and brain. At the basis of the bloodbrain barrier are, next to an elaborate transporting machinery, tight junctions which create not only a paracellular diffusion constraint but also enable vectorial transport across the endothelial monolayer. Generally, tight junctions not only represent a cellcell adhesion structure, but integrate various signaling pathways via large multiprotein complexes, thereby impacting upon processes such as cell proliferation, cytoskeletal rearrangement, and transcriptional control. This review provides an overview of tight junction morphology and discusses our current understanding of the molecular composition of endothelial tight junctions at the blood-brain barrier.
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Traumatic Brain Injury and Blood-Brain Barrier Cross-Talk
Traumatic brain injury, often referred to as the “silent epidemic,” is a nondegenerative, non-congenital insult to the brain due to a blow or penetrating object that disrupts the function of the brain leading to permanent or temporary impairment of cognition, physical and psychosocial functions. Traumatic brain injury usually has poor prognosis for long-term treatment and is a major cause of mortality and morbidity worldwide; approximately 10 million deaths and/or hospitalizations annually are directly related to traumatic brain injury. Traumatic brain injury involves primary and secondary insults. Primary injury occurs during the initial insult, and results from direct or indirect force applied to the physical structures of the brain. Secondary injury is characterized by longer-term degeneration of neurons, glial cells, and vascular tissues due to activation of several proteases, glutamate and pro-inflammatory cytokine secretion. In addition, there is growing evidence that the blood-brain barrier is involved in the course of traumatic brain injury pathophysiology and has detrimental effects on the overall pathology of brain trauma, as will be discussed in this work.
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Pathophysiology of Blood-Brain Barrier in Brain Injury in Cold and Hot Environments: Novel Drug Targets for Neuroprotection
The blood-brain barrier (BBB) plays a pivotal role in the maintenance of central nervous system function in health and disease. Thus, in almost all neurodegenerative, traumatic or metabolic insults BBB breakdown occurs, allowing entry of serum proteins into the brain fluid microenvironment with subsequent edema formation and cellular injury. Accordingly, pharmacological restoration of BBB function will lead to neurorepair. However, brain injury which occurs following blast, bullet wounds, or knife injury appears to initiate different sets of pathophysiological responses. Moreover, other local factors at the time of injury such as cold or elevated ambient temperatures could also impact the final outcome. Obviously, drug therapy applied to different kinds of brain trauma occurring at either cold or hot environments may respond differently. This is largely due to the fact that internal defense mechanisms of the brain, gene expression, release of neurochemicals and binding of drugs to specific receptors are affected by external ambient temperature changes. These factors may also affect BBB function and development of edema formation after brain injury. In this review, the effects of seasonal exposure to heat and cold on traumatic brain injury using different models i.e., concussive brain injury and cerebral cortical lesion, on BBB dysfunction in relation to drug therapy are discussed. Our observations clearly suggest that closed head injury and open brain injury are two different entities and the external hot or cold environments affect both of them remarkably. Thus, effective pharmacological therapeutic strategies should be designed with these views in mind, as military personnel often experience blunt or penetrating head injuries in either cold or hot environments.
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Mast Cell – Glia Dialogue in Chronic Pain and Neuropathic Pain: Blood-Brain Barrier Implications
More LessMast cells and microglia, working singly and in partnership, produce proinflammatory agents which play key roles in a wide array of nervous system disorders. Such neuroinflammatory settings may compromise integrity of both the blood-nerve barrier and blood-brain barrier (BBB) and blood-spinal cord barrier. While both belong to the innate immune system mast cells are far more ubiquitous, are resident in peripheral nerves and the central nervous system, and can influence blood-nerve barrier characteristics. Mast cells, being near the perivasculature especially within the dura, on the brain side of the BBB, are strategically located to play havoc with the BBB. Mast cells and glia are endowed with homeostatic mechanisms/molecules which come into play following tissue damage. These include the N-acylethanolamine family, especially N-palmitoylethanolamine, which is posited to be a key player in maintaining cellular homeostasis against external stressors provoking, for example, inflammation. This review is intended as an overview covering the pathobiology of neuroinflammation in the context of mast cells and microglia, their role in BBB integrity, and therapeutic perspectives in targeting these cells to preserve BBB function.
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Potential Use of Nanomedicine for Drug Delivery Across the Blood-Brain Barrier in Healthy and Diseased Brain
The research of efficacious non-invasive therapies for the treatment of brain diseases represents a huge challenge, as people affected by disorders of the central nervous system (CNS) will significantly increase. Moreover, the blood-brain barrier is a key factor in hampering a number of effective drugs to reach the CNS. This review is therefore focusing on possible interventions of nanomedicine-based approaches in selected diseases affecting the CNS. A wide overview of the most outstanding results on preclinical evaluations of the potential of nanomedicine in brain diseases (i.e. brain tumor, Alzheimer, Parkinson, epilepsy and others) is given, with highlights on the data with relevant interest and real possibility in translation from bench-to-bedside. Moreover, a critical evaluation on the rationale in planning nanosystems to target specific brain pathologies is described, opening the path to a more structured and pathology-tailored design of nanocarriers.
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Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair
The blood-brain barrier (BBB) is a physiological regulator of transport of essential items from blood to brain for the maintenance of homeostasis of the central nervous system (CNS) within narrow limits. The BBB is also responsible for export of harmful or metabolic products from brain to blood to keep the CNS fluid microenvironment healthy. However, noxious insults to the brain caused by trauma, ischemia or environmental/chemical toxins alter the BBB function to small as well as large molecules e.g., proteins. When proteins enter the CNS fluid microenvironment, development of brain edema occurs due to altered osmotic balance between blood and brain. On the other hand, almost all neurodegenerative diseases and traumatic insults to the CNS and subsequent BBB dysfunction lead to edema formation and cell injury. To treat these brain disorders suitable drug therapy reaching their brain targets is needed. However, due to edema formation or only a focal disruption of the BBB e.g., around brain tumors, many drugs are unable to reach their CNS targets in sufficient quantity. This results in poor therapeutic outcome. Thus, new technology such as nanodelivery is needed for drugs to reach their CNS targets and be effective. In this review, use of nanowires as a possible novel tool to enhance drug delivery into the CNS in various disease models is discussed based on our investigations. These data show that nanowired delivery of drugs may have superior neuroprotective ability to treat several CNS diseases effectively indicating their role in future therapeutic strategies.
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Involvement of the Blood-Brain Barrier in Metabolic Regulation
Authors: Abba J. Kastin and Weihong PanPertinent to pandemic obesity, the discovery of endogenous peptides that affect the ingestion of food has led to the question of how these ingestive peptides exert their actions in the brain. Whereas peripheral sources provide a ready reserve, the availability of ingestive peptides to their central nervous system targets can be regulated by the blood-brain barrier (BBB). Some of the peptides/polypeptides are transported by saturable mechanisms from blood to brain. Examples include leptin, insulin, mahogany, and pancreatic polypeptide. Some enter the brain by passive diffusion, such as neuropeptide Y, orexin A, cocaine- and amphetamine-regulated transcript, cyclo His-Pro, and amylin. Some others may have essentially no penetration of the BBB; this class includes agouti-related protein, melanin-concentrating hormone, and urocortin. The regulatory function of the BBB can be seen in various physiological states. Hyperglycemia may upregulate transport systems for leptin, urocortin, and galanin-like peptide, whereas fasting can down-regulate those for leptin and galanin-like peptide. Thus, the BBB plays a dynamic role in modulating the passage of ingestive peptides from blood to brain.
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Breakdown of Blood-Brain and Blood-Spinal Cord Barriers During Acute Methamphetamine Intoxication: Role of Brain Temperature
Authors: Eugene A. Kiyatkin and Hari S. SharmaMethamphetamine (METH) is a powerful and often-abused stimulant with potent addictive and neurotoxic properties. While it is generally believed that structural brain damage induced by METH results from oxidative stress, in this work we present data suggesting robust disruption of blood-brain and blood-spinal cord barriers during acute METH intoxication in rats. We demonstrate the relationships between METH-induced brain hyperthermia and widespread but structure-specific barrier leakage, acute glial cell activation, changes in brain water and ionic homeostasis, and structural damage of different types of cells in the brain and spinal cord. Therefore, METH-induced leakage of the blood-brain and blood-spinal cord barriers is a significant contributor to different types of functional and structural brain abnormalities that determine acute toxicity of this drug and possibly neurotoxicity during its chronic use.
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Spinal Cord Injury Changes Cytokine Transport
Authors: Weihong Pan and Abba J. KastinHere we summarize three aspects of our understanding of the interactions of cytokines and neurotrophic peptides/proteins with the blood-brain and bloodspinal cord barriers (BBB): (a) pharmacokinetic analysis that has been reported for native cytokines and neurotrophic peptides/proteins; (b) landmark work on conjugated proteins to enhance their delivery across the normal BBB; and (c) regulatory changes under pathophysiological conditions in rodents, particularly after spinal cord injury (SCI). First, though the BBB restricts the permeation of large proteins, some cytokines and neurotrophic peptides/proteins in the periphery can reach the central nervous system (CNS) by specific transport systems. Moreover, SCI and some other disease processes may regulate these transport systems. The significance of studies of the transport systems is obvious because of the biological impact of these molecules on the CNS in health and disease. We have characterized the pharmacokinetic characteristics of some stable cytokines and neurotrophic peptides/proteins in mice after intravenous administration and also in the setting of in situ brain perfusion. In the particular case of SCI, there are time- and regionspecific changes of BBB permeability and transport systems. Tumor necrosis factor-α, a cytokine with dual actions in regeneration of the spinal cord, has a slow basal influx into the brain and spinal cord. After SCI, the increase in the entry of tumor necrosis factor-α to the CNS differs from leakage after BBB disruption and is related to upregulation of the transport system in a unique temporal and regional pattern. Overall, the permeation of cytokines across the BBB can be mediated by specific transport systems. The regulation of transport in pathophysiological conditions affects the extent of neuroinflammation and is implicated in neuroregeneration.
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Merging Transport Data for Choroid Plexus with Blood-Brain Barrier to Model CNS Homeostasis and Disease More Effectively
Authors: Conrad Johanson and Nancy JohansonRobust modeling of CNS transport integrates molecular fluxes at the microvascular blood-brain barrier and epithelial choroid plexus blood-cerebrospinal fluid (CSF) barrier. Normal activity of solute transporters, channels and aquaporins, in the cerebral endothelium and choroidal epithelium, sets the microenvironment composition for neurons and glia. Conversely, perturbed transport/permeability at the barrier interfaces causes interstitial fluid dyshomeostasis (e.g. edema) arising in neural disorders. Critically-important transependymal solute/water distribution between brain and CSF needs more attention. This treatise encourages procuring transport data simultaneously for blood-brain barrier, blood-CSF barrier and CSF. In situ perfusion and multicompartmental analyses (tracers, microdialysis) provide dynamic assessments of molecular transfer among various CNS regions. Diffusion, active transport and convection are distorted by disease- and age-associated alterations in barrier permeability and CSF turnover (sink action). Clinical complications result from suboptimal conveyance of micronutrients (folate), catabolites (β-amyloid) and therapeutic agents (antibiotics) within the CNS. Neurorestorative therapies for stroke, traumatic brain injury, multiple sclerosis and brain tumors are facilitated by insight on molecular and cellular trafficking through the choroid plexus-CSF nexus. Knowledge is needed about fluxes of growth factors, neurotrophins, hormones and leukocytes from ventricular CSF into the hippocampus, subventricular zone and hypothalamus. CSF and brain removal of potentially toxic catabolites and neuropeptides merits further investigation to manage the degeneration of Alzheimer’s disease and normal pressure hydrocephalus. Novel therapies will rely on delineating peptide and drug distributions across the blood-brain barrier and choroid plexus-CSF, and how they modulate the intervening neural-glial networks and neurogenic sites. Multicompartmental transport modeling is key to devising specific pharmacologic targeting and thus impactful CSF translational research for CNS disorders.
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Neuroprotection by Methylene Blue in Cerebral Global Ischemic Injury Induced Blood-Brain Barrier Disruption and Brain Pathology: A Review
Authors: Lars Wiklund, Aruna Sharma and Hari Shanker SharmaTransient global ischemic cerebral injury is a consequence of cardiac arrest and accounts for approximately 450,000 annual deaths with a mortality of approximately 90%. Serious morbidity follows for many of the survivors and up to 16% of patients achieving restoration of spontaneous circulation develop brain death. Other survivors are left with persistent cognitive impairment such as memory and sensimotor deficits, reducing quality of life and resulting in heavy costs on society. Many studies over the years have been devoted to improving outcome after cardiac arrest and have, to a certain degree succeeded, especially locally in areas where improvement of ambulance organizations have been effective. In spite of this serious problems remain and the chances of cerebral survival need to increase if over-all results, i.e. survival as well as cognitive function, are to improve. Methylene blue, a textile dye synthesized in the late 19th century has also been used in medicine for different purposes. One of its effects is to increase systemic blood pressure, but other effects have been documented, among which are its neuroprotective effects well-noted during the last few years. In this review we have appraised these findings in relation to global ischemic injury.
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Blood-Brain Barrier Changes in High Altitude
Authors: José V. Lafuente, Garazi Bermudez, Lorena Camargo-Arce and Susana BulnesCerebral syndromes related to high-altitude exposure are becoming more frequent as the number of trips to high altitudes has increased in the last decade. The commonest symptom is headache, followed by acute mountain sickness (AMS) and high-altitude cerebral edema (HACE), which can be fatal. The pathophysiology of these syndromes is not fully understood. The classical "tight-fit hypothesis" posits that there are some anatomical variations that would obstruct the sinovenous outflow and worsen vasogenic edema and intracranial hypertension reactive to hypoxia. This could explain microhemorrhages seen in autopsies. However, recent magnetic resonance imaging studies have demonstrated some components of cytotoxic edema in HACE absent in AMS, suggesting a dysfunction in water balance at the cellular level. Currently, the "red-ox theory" supports trigemino-vascular system activation by free radicals formed after hypoxia and the consequent oxidative stress cascades. Apart from trigemino-vascular system activation, free radicals can also provoke membrane destabilisation mediated by lipid peroxidation, inflammation, and local hypoxia inducible factor-1α and vascular endothelial growth factor activation, resulting in gross blood-brain barrier (BBB) dysfunction. Besides alterations in endothelial cells such as increased pinocytotic vesicles and disassembly of interendothelial tight junction proteins, capillary permeability may also increase with subsequent swelling of astrocyte end-feet. In conclusion, although the pathophysiology of AMS and HACE is not completely understood, recent evidence proposes a multifactorial entity, with brain swelling and compromise of the BBB considered to play an important role. A fuller comprehension of these processes is crucial to reduce and prevent BBB alterations during high-altitude exposure.
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Volumes & issues
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Volume 23 (2024)
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Volume 22 (2023)
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Volume 21 (2022)
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Volume 20 (2021)
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Volume 19 (2020)
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Volume 18 (2019)
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Volume 17 (2018)
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Volume 16 (2017)
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Volume 15 (2016)
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Volume 14 (2015)
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Volume 13 (2014)
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Volume 12 (2013)
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Volume 11 (2012)
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Volume 10 (2011)
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Volume 9 (2010)
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Volume 8 (2009)
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Volume 7 (2008)
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Volume 6 (2007)
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Volume 5 (2006)