Tight Junction Modulating Bioprobes for Drug Delivery System to the Brain: A Review

The blood-brain barrier (BBB), which is composed of endothelial cells, pericytes, astrocytes, and neurons, separates the brain extracellular fluid from the circulating blood, and maintains the homeostasis of the central nervous system (CNS). The BBB endothelial cells have well-developed tight junctions (TJs) and express specific polarized transport systems to tightly control the paracellular movements of solutes, ions, and water. There are two types of TJs: bicellular TJs (bTJs), which is a structure at the contact of two cells, and tricellular TJs (tTJs), which is a structure at the contact of three cells. Claudin-5 and angulin-1 are important components of bTJs and tTJs in the brain, respectively. Here, we review TJ-modulating bioprobes that enable drug delivery to the brain across the BBB, focusing on claudin-5 and angulin-1.

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The blood–brain barrier

Southern African Journal of Anaesthesia and Analgesia ◽

10.36303/sajaa.2020.26.6.s3.2533 ◽

2020 ◽

pp. S32-S34

Author(s):

S Dingezweni

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Transport Systems ◽

Barrier Structure ◽

Waste Products ◽

Blood Brain ◽

The Central Nervous System ◽

The Brain

The blood–brain barrier (BBB) is a dynamic barrier essential for central nervous system interstitial fluid separation from circulating blood. This dynamic separation ensures maintenance of neuronal microenvironment homeostasis against that of the everchanging in solutes and toxin concentration in circulating blood. The blood–brain barrier structure is complex, it has multiple contributors, such as specialised blood microvascular endothelium, neurons, astrocytes and pericytes. Transfer of essential nutrients to the brain and waste products from the brain to circulating blood is tightly regulated and facilitated by a large surface area and specialised transport systems. It is not only the physical characteristics of the barrier that assist in maintenance of neuronal microenvironment, biochemical substances and the high trans endothelial electrical resistance also play a major role. Circumventricular organs are those parts of the central nervous system lacking the blood–brain barrier. These are essential for optimum central nervous system interaction with circulating blood directly or using neurotransmitters. Primary or secondary central nervous system pathological states, such as infective and noninfective causes, directly or indirectly induce biochemical mediators that may disrupt and alter blood–brain barrier structure and function. Understanding of the blood–brain barrier anatomy and physiology assists in developing treatment methods to overcome degenerative and pathological states negatively affecting the central nervous system.

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Nanotherapeutics in Neuropathologies: Obstacles, Challenges and Recent Advancements in CNS Targeted Drug Delivery Systems

Current Neuropharmacology ◽

10.2174/1570159x18666200807143526 ◽

2020 ◽

Vol 18 ◽

Author(s):

Vimal Patel ◽

Vishal Chavda ◽

Jigar Shah

Keyword(s):

Drug Delivery ◽

Central Nervous System ◽

Nervous System ◽

Targeted Drug Delivery ◽

Drug Dose ◽

The Body ◽

Brain Drug Delivery ◽

The Central Nervous System ◽

Targeted Drug ◽

The Brain

: Neurology and associated nanotherapeutics is a complex field in terms of therapeutics and neurological disorder complexity. Brain is an intricate appendage and requires more precise embattled treatment for the particular diseases and hence it’s a broad scale for developing more targeted drug deliveries. The brain is one of the most inaccessible tissues of the body due to the existence of the blood-brain barrier (BBB), thus delivery of drugs inside the brain is a striking dare and it is also tricky to treat central nervous system (CNS) complications pharmacologically. The therapeutic aspiration is to accomplish a lowest drug meditation in the brain tissues so as to gain favoured therapeutic results. To devastate this obstacle, nanotechnology is engaged in the field of targeted brain drug delivery and neuropathology targeting. These carriers hold myriad ability as they may augment the drug delivery into the brain by shielding them from degradation and prolonging their transmission in the blood, as well as promoting their transport through the BBB. Nanopharmaceuticals are quickly sprouting as new avenue that is engaged with the drug-loaded nanocarriers to demonstrate unique physicochemical properties and tiny size range for penetrating into the central nervous system. The enchantment behind their therapeutic achievement is the condensed drug dose and inferior toxicity, whereby restricting the therapeutic compound to the specific site. Therefore, in this article we have tried to recapitulate the advances the novel scopes for the brain targeted drug delivery for complex neurological disorders.

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Cryptococcus neoformans Promotes Its Transmigration into the Central Nervous System by Inducing Molecular and Cellular Changes in Brain Endothelial Cells

Infection and Immunity ◽

10.1128/iai.00554-13 ◽

2013 ◽

Vol 81 (9) ◽

pp. 3139-3147 ◽

Cited By ~ 36

Author(s):

Kiem Vu ◽

Richard A. Eigenheer ◽

Brett S. Phinney ◽

Angie Gelli

Keyword(s):

Central Nervous System ◽

Endothelial Cells ◽

Nervous System ◽

Human Brain ◽

Cryptococcus Neoformans ◽

Brain Endothelial Cells ◽

Brain Endothelium ◽

Content Type ◽

The Central Nervous System ◽

The Brain

ABSTRACTCryptococcusspp. cause fungal meningitis, a life-threatening infection that occurs predominately in immunocompromised individuals. In order forCryptococcus neoformansto invade the central nervous system (CNS), it must first penetrate the brain endothelium, also known as the blood-brain barrier (BBB). Despite the importance of the interrelation betweenC. neoformansand the brain endothelium in establishing CNS infection, very little is known about this microenvironment. Here we sought to resolve the cellular and molecular basis that defines the fungal-BBB interface during cryptococcal attachment to, and internalization by, the human brain endothelium. In order to accomplish this by a systems-wide approach, the proteomic profile of human brain endothelial cells challenged withC. neoformanswas resolved using a label-free differential quantitative mass spectrometry method known as spectral counting (SC). Here, we demonstrate that as brain endothelial cells associate with, and internalize, cryptococci, they upregulate the expression of several proteins involved with cytoskeleton, metabolism, signaling, and inflammation, suggesting that they are actively signaling and undergoing cytoskeleton remodeling via annexin A2, S100A10, transgelin, and myosin. Transmission electronic microscopy (TEM) analysis demonstrates dramatic structural changes in nuclei, mitochondria, the endoplasmic reticulum (ER), and the plasma membrane that are indicative of cell stress and cell damage. The translocation of HMGB1, a marker of cell injury, the downregulation of proteins that function in transcription, energy production, protein processing, and the upregulation of cyclophilin A further support the notion thatC. neoformanselicits changes in brain endothelial cells that facilitate the migration of cryptococci across the BBB and ultimately induce endothelial cell necrosis.

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Cryptococcal Yeast Cells Invade the Central Nervous System via Transcellular Penetration of the Blood-Brain Barrier

Infection and Immunity ◽

10.1128/iai.72.9.4985-4995.2004 ◽

2004 ◽

Vol 72 (9) ◽

pp. 4985-4995 ◽

Cited By ~ 152

Author(s):

Yun C. Chang ◽

Monique F. Stins ◽

Michael J. McCaffery ◽

Georgina F. Miller ◽

Dan R. Pare ◽

...

Keyword(s):

Central Nervous System ◽

Endothelial Cells ◽

Nervous System ◽

Blood Brain Barrier ◽

Yeast Cells ◽

Brain Barrier ◽

Blood Brain ◽

The Central Nervous System ◽

The Brain

ABSTRACT Cryptococcal meningoencephalitis develops as a result of hematogenous dissemination of inhaled Cryptococcus neoformans from the lung to the brain. The mechanism(s) by which C. neoformans crosses the blood-brain barrier (BBB) is a key unresolved issue in cryptococcosis. We used both an in vivo mouse model and an in vitro model of the human BBB to investigate the cryptococcal association with and traversal of the BBB. Exposure of human brain microvascular endothelial cells (HBMEC) to C. neoformans triggered the formation of microvillus-like membrane protrusions within 15 to 30 min. Yeast cells of C. neoformans adhered to and were internalized by the HBMEC, and they crossed the HBMEC monolayers via a transcellular pathway without affecting the monolayer integrity. The histopathology of mouse brains obtained after intravenous injection of C. neoformans showed that the yeast cells either were associated with endothelial cells or escaped from the brain capillary vessels into the neuropil by 3 h. C. neoformans was found in the brain parenchyma away from the vessels by 22 h. Association of C. neoformans with the choroid plexus, however, was not detected during up to 10 days of observation. Our findings indicate that C. neoformans cells invade the central nervous system by transcellular crossing of the endothelium of the BBB.

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GF120918, a P-Glycoprotein Modulator, Increases the Concentration of Unbound Amprenavir in the Central Nervous System in Rats

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.7.2284-2286.2002 ◽

2002 ◽

Vol 46 (7) ◽

pp. 2284-2286 ◽

Cited By ~ 48

Author(s):

Jeffrey E. Edwards ◽

Kenneth R. Brouwer ◽

Patrick J. McNamara

Keyword(s):

Central Nervous System ◽

Human Immunodeficiency Virus ◽

Nervous System ◽

Protease Inhibitors ◽

Extracellular Fluid ◽

Human Immunodeficiency Virus Protease ◽

P Glycoprotein ◽

Immunodeficiency Virus ◽

The Central Nervous System ◽

The Brain

ABSTRACT The goal of this study was to determine the distribution of unbound amprenavir in the central nervous system (CNS) of rats. The concentration of unbound amprenavir in the extracellular fluid of the brain and the blood was examined in the presence and absence of the MDR modulator GF120918 by microdialysis. The brain-to-blood ratio of amprenavir in the absence and presence of GF120918 was found to be significantly different (P < 0.003; 0.076 and 0.617, respectively). The use of the MDR modulator GF120918 could potentially increase the penetration of human immunodeficiency virus protease inhibitors into the CNS.

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Glucuronyl 3-sulfate occurs exclusively on distal unmyelinated terminals of selected sensory neurons in the peripheral nervous system

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100141160 ◽

1995 ◽

Vol 53 ◽

pp. 958-959

Author(s):

S.S. Spicer ◽

B.A. Schulte

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Cerebral Cortex ◽

Peripheral Nervous System ◽

Sensory Neurons ◽

Sensory Nerves ◽

Tissue Antigens ◽

The Central Nervous System ◽

The Brain ◽

Leu 7

Generation of monoclonal antibodies (MAbs) against tissue antigens has yielded several (VC1.1, HNK- 1, L2, 4F4 and anti-leu 7) which recognize the unique sugar epitope, glucuronyl 3-sulfate (Glc A3- SO4). In the central nervous system, these MAbs have demonstrated Glc A3-SO4 at the surface of neurons in the cerebral cortex, the cerebellum, the retina and other widespread regions of the brain.Here we describe the distribution of Glc A3-SO4 in the peripheral nervous system as determined by immunostaining with a MAb (VC 1.1) developed against antigen in the cat visual cortex. Outside the central nervous system, immunoreactivity was observed only in peripheral terminals of selected sensory nerves conducting transduction signals for touch, hearing, balance and taste. On the glassy membrane of the sinus hair in murine nasal skin, just deep to the ringwurt, VC 1.1 delineated an intensely stained, plaque-like area (Fig. 1). This previously unrecognized structure of the nasal vibrissae presumably serves as a tactile end organ and to our knowledge is not demonstrable by means other than its selective immunopositivity with VC1.1 and its appearance as a densely fibrillar area in H&E stained sections.

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Central Nerve System Impairment, AMA Guides, Sixth Edition: An Overview

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2018.janfeb03 ◽

2018 ◽

Vol 23 (1) ◽

pp. 10-13

Author(s):

James B. Talmage ◽

Jay Blaisdell

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Neurological Impairment ◽

Sixth Edition ◽

Central Nerve System ◽

The Central Nervous System ◽

The One ◽

Nerve System ◽

The Brain

Abstract Injuries that affect the central nervous system (CNS) can be catastrophic because they involve the brain or spinal cord, and determining the underlying clinical cause of impairment is essential in using the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), in part because the AMA Guides addresses neurological impairment in several chapters. Unlike the musculoskeletal chapters, Chapter 13, The Central and Peripheral Nervous System, does not use grades, grade modifiers, and a net adjustment formula; rather the chapter uses an approach that is similar to that in prior editions of the AMA Guides. The following steps can be used to perform a CNS rating: 1) evaluate all four major categories of cerebral impairment, and choose the one that is most severe; 2) rate the single most severe cerebral impairment of the four major categories; 3) rate all other impairments that are due to neurogenic problems; and 4) combine the rating of the single most severe category of cerebral impairment with the ratings of all other impairments. Because some neurological dysfunctions are rated elsewhere in the AMA Guides, Sixth Edition, the evaluator may consult Table 13-1 to verify the appropriate chapter to use.

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Faculty Opinions recommendation of The brain as an immune privileged site: dendritic cells of the central nervous system inhibit T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1014090.200835 ◽

2003 ◽

Author(s):

Magdalena Plebanski

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

The Central Nervous System ◽

The Brain ◽

Privileged Site

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RAS in the Central Nervous System: Potential Role in Neuropsychiatric Disorders

Current Medicinal Chemistry ◽

10.2174/0929867325666180226102358 ◽

2018 ◽

Vol 25 (28) ◽

pp. 3333-3352 ◽

Cited By ~ 21

Author(s):

Natalia Pessoa Rocha ◽

Ana Cristina Simoes e Silva ◽

Thiago Ruiz Rodrigues Prestes ◽

Victor Feracin ◽

Caroline Amaral Machado ◽

...

Keyword(s):

Blood Pressure ◽

Central Nervous System ◽

Nervous System ◽

Therapeutic Potential ◽

Neuropsychiatric Disorders ◽

Extensive Literature ◽

Ang Ii ◽

Mas Receptor ◽

The Central Nervous System ◽

The Brain

Background: The Renin-Angiotensin System (RAS) is a key regulator of cardiovascular and renal homeostasis, but also plays important roles in mediating physiological functions in the central nervous system (CNS). The effects of the RAS were classically described as mediated by angiotensin (Ang) II via angiotensin type 1 (AT1) receptors. However, another arm of the RAS formed by the angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and the Mas receptor has been a matter of investigation due to its important physiological roles, usually counterbalancing the classical effects exerted by Ang II. Objective: We aim to provide an overview of effects elicited by the RAS, especially Ang-(1-7), in the brain. We also aim to discuss the therapeutic potential for neuropsychiatric disorders for the modulation of RAS. Method: We carried out an extensive literature search in PubMed central. Results: Within the brain, Ang-(1-7) contributes to the regulation of blood pressure by acting at regions that control cardiovascular functions. In contrast with Ang II, Ang-(1-7) improves baroreflex sensitivity and plays an inhibitory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to blood pressure regulation, but also acts as a neuroprotective component of the RAS, for instance, by reducing cerebral infarct size, inflammation, oxidative stress and neuronal apoptosis. Conclusion: Pre-clinical evidence supports a relevant role for ACE2/Ang-(1-7)/Mas receptor axis in several neuropsychiatric conditions, including stress-related and mood disorders, cerebrovascular ischemic and hemorrhagic lesions and neurodegenerative diseases. However, very few data are available regarding the ACE2/Ang-(1-7)/Mas receptor axis in human CNS.

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