scholarly journals Biomaterials for Drugs Nose–Brain Transport: A New Therapeutic Approach for Neurological Diseases

Materials ◽  
2021 ◽  
Vol 14 (7) ◽  
pp. 1802
Author(s):  
Roberta Cassano ◽  
Camilla Servidio ◽  
Sonia Trombino
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Stimuli Responsive ◽  
Neurodegenerative Process ◽  
Blood Brain ◽  
Global Health Issue ◽  
The Brain

In the last years, neurological diseases have resulted in a global health issue, representing the first cause of disability worldwide. Current therapeutic approaches against neurological disorders include oral, topical, or intravenous administration of drugs and more invasive techniques such as surgery and brain implants. Unfortunately, at present, there are no fully effective treatments against neurodegenerative diseases, because they are not associated with a regeneration of the neural tissue but rather act on slowing the neurodegenerative process. The main limitation of central nervous system therapeutics is related to their delivery to the nervous system in therapeutic quantities due to the presence of the blood–brain barrier. In this regard, recently, the intranasal route has emerged as a promising administration site for central nervous system therapeutics since it provides a direct connection to the central nervous system, avoiding the passage through the blood–brain barrier, consequently increasing drug cerebral bioavailability. This review provides an overview of the nose-to-brain route: first, we summarize the anatomy of this route, focusing on the neural mechanisms responsible for the delivery of central nervous system therapeutics to the brain, and then we discuss the recent advances made on the design of intranasal drug delivery systems of central nervous system therapeutics to the brain, focusing in particular on stimuli-responsive hydrogels.

scholarly journals Central nervous system diseases associated with blood brain barrier breakdown - A Comprehensive update of existing literatures

2020 ◽  
Vol 4 (2) ◽  
pp. 053-062
Author(s):  
Dutta Rajib
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Barrier Breakdown ◽  
The Brain ◽  
Blood Brain Barrier Breakdown

Blood vessels that supply and feed the central nervous system (CNS) possess unique and exclusive properties, named as blood–brain barrier (BBB). It is responsible for tight regulation of the movement of ions, molecules, and cells between the blood and the brain thereby maintaining controlled chemical composition of the neuronal milieu required for appropriate functioning. It also protects the neural tissue from toxic plasma components, blood cells and pathogens from entering the brain. In this review the importance of BBB and its disruption causing brain pathology and progression to different neurological diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) etc. will be discussed.

Understanding the Physiology of the Blood-Brain Barrier: In Vitro Models

Physiology ◽  
1998 ◽  
Vol 13 (6) ◽  
pp. 287-293 ◽  
Author(s):  
Gerald A. Grant ◽  
N. Joan Abbott ◽  
Damir Janigro
Keyword(s):  
Central Nervous System ◽  
Tissue Culture ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
In Vitro Models ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Tissue Culture ◽  
The Brain

Endothelial cells exposed to inductive central nervous system factors differentiate into a blood-brain barrier phenotype. The blood-brain barrier frequently obstructs the passage of chemotherapeutics into the brain. Tissue culture systems have been developed to reproduce key properties of the intact blood-brain barrier and to allow for testing of mechanisms of transendothelial drug permeation.

scholarly journals Tembusu Virus entering the central nervous system caused nonsuppurative encephalitis without disrupting the blood-brain barrier

2021 ◽  
Author(s):  
Sheng Yang ◽  
Yufei Huang ◽  
Yonghong Shi ◽  
Xuebing Bai ◽  
Ping Yang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Neurological Symptoms ◽  
Brain Barrier ◽  
Poultry Industry ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Tembusu Virus ◽  
The Brain

Tembusu Virus (TMUV) is an emerging and re-emerging zoonotic pathogen that adversely affects poultry industry in recent years. TMUV disease is characterized by nonsuppurative encephalitis in ducklings. The duckling infection model was established to study the mechanism of TMUV crossing the blood-brain barrier (BBB) into the central nervous system (CNS). Here, we showed that no obvious clinical symptoms and enhancement of BBB permeability occurred at the early stage of infection (3∼5 dpi). While simultaneously virus particles were observed by transmission electron microscopy in the brain, inducing the accumulation of inflammatory cytokines. Neurological symptoms and disruption of BBB appeared at the intermediate stage of infection (7∼9 dpi). It was confirmed that TMUV could survive and propagate in brain microvascular endothelial cells (BMECs), but did not affect the permeability of BBB in vivo and in vitro at an early date. In conclusion, TMUV enters the CNS then causes encephalitis, and finally destruct the BBB, which may be due to the direct effect of TMUV on BMECs and the subsequent response of “inflammatory storm”. IMPORTANCE The TMUV disease has caused huge losses to the poultry industry in Asia, which is potentially harmful to public health. Neurological symptoms and their sequelae are the main characters of this disease. However, the mechanism of how this virus enters the brain and causes encephalitis is unclear. In this study, we confirmed that the virus entered the CNS and then massively destroyed BBB and the BBB damage was closely associated with the subsequent outbreak of inflammation. TMUV may enter the CNS through the transcellular and “Trojan horse” pathways. These findings can fill the knowledge gap in the pathogenesis of TMUV-infected poultry and be benefit for the treatment of TMUV disease. What’s more, TMUV is a representative to study the infection of avian flavivirus. Therefore, our studies have significances both for understanding of the full scope of mechanisms of TMUV and other flavivirus infection, and conceivably, for therapeutics.

scholarly journals Modulation of Sialic Acid Dependence Influences the Central Nervous System Transduction Profile of Adeno-associated Viruses

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Blake H. Albright ◽  
Katherine E. Simon ◽  
Minakshi Pillai ◽  
Garth W. Devlin ◽  
Aravind Asokan
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Sialic Acid ◽  
Blood Brain Barrier ◽  
Viral Vectors ◽  
Variable Region ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

ABSTRACT Central nervous system (CNS) transduction by systemically administered recombinant adeno-associated viral (AAV) vectors requires crossing the blood-brain barrier (BBB). We recently mapped a structural footprint on the AAVrh.10 capsid, which, when grafted onto the AAV1 capsid (AAV1RX), enables viral transport across the BBB; however, the underlying mechanisms remain unknown. Here, we establish through structural modeling that this footprint overlaps in part the sialic acid (SIA) footprint on AAV1. We hypothesized that altered SIA-capsid interactions may influence the ability of AAV1RX to transduce the CNS. Using AAV1 variants with altered SIA footprints, we map functional attributes of these capsids to their relative SIA dependence. Specifically, capsids with ablated SIA binding can penetrate and transduce the CNS with low to moderate efficiency. In contrast, AAV1 shows strong SIA dependency and does not transduce the CNS after systemic administration and, instead, transduces the vasculature and the liver. The AAV1RX variant, which shows an intermediate SIA binding phenotype, effectively enters the brain parenchyma and transduces neurons at levels comparable to the level of AAVrh.10. In corollary, the reciprocal swap of the AAV1RX footprint onto AAVrh.10 (AAVRX1) attenuated CNS transduction relative to that of AAVrh.10. We conclude that the composition of residues within the capsid variable region 1 (VR1) of AAV1 and AAVrh.10 profoundly influences tropism, with altered SIA interactions playing a partial role in this phenotype. Further, we postulate a Goldilocks model, wherein optimal glycan interactions can influence the CNS transduction profile of AAV capsids. IMPORTANCE Understanding how viruses cross the blood-brain barrier can provide insight into new approaches to block infection by pathogens or the ability to exploit these pathways for designing new recombinant viral vectors for gene therapy. In this regard, modulation of virus-carbohydrate interactions by mutating the virion shell can influence the ability of recombinant viruses to cross the vascular barrier, enter the brain, and enable efficient gene transfer to neurons.

scholarly journals Novel Blood–Brain Barrier Shuttle Peptides Discovered through the Phage Display Method

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 874 ◽  
Author(s):  
Petra Majerova ◽  
Jozef Hanes ◽  
Dominika Olesova ◽  
Jakub Sinsky ◽  
Emil Pilipcinec ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Phage Display ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Phage Display Technology ◽  
Blood Brain ◽  
Display Technology ◽  
The Brain

Delivery of therapeutic agents into the brain is a major challenge in central nervous system drug development. The blood–brain barrier (BBB) prevents access of biotherapeutics to their targets in the central nervous system and, therefore, prohibits the effective treatment of many neurological disorders. To find blood–brain barrier shuttle peptides that could target therapeutics to the brain, we applied a phage display technology on a primary endothelial rat cellular model. Two identified peptides from a 12 mer phage library, GLHTSATNLYLH and VAARTGEIYVPW, were selected and their permeability was validated using the in vitro BBB model. The permeability of peptides through the BBB was measured by ultra-performance liquid chromatography-tandem mass spectrometry coupled to a triple-quadrupole mass spectrometer (UHPLC-MS/MS). We showed higher permeability for both peptides compared to N–C reversed-sequence peptides through in vitro BBB: for peptide GLHTSATNLYLH 3.3 × 10−7 cm/s and for peptide VAARTGEIYVPW 1.5 × 10−6 cm/s. The results indicate that the peptides identified by the in vitro phage display technology could serve as transporters for the administration of biopharmaceuticals into the brain. Our results also demonstrated the importance of proper BBB model for the discovery of shuttle peptides through phage display libraries.

scholarly journals Blood-brain barrier-restricted translocation of Toxoplasma gondii from cortical capillaries

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Gabriela C Olivera ◽  
Emily C Ross ◽  
Christiane Peuckert ◽  
Antonio Barragan
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Toxoplasma Gondii ◽  
Blood Brain Barrier ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Cortical Capillaries ◽  
The Brain

The cellular barriers of the central nervous system proficiently protect the brain parenchyma from infectious insults. Yet, the single-celled parasite Toxoplasma gondii commonly causes latent cerebral infection in humans and other vertebrates. Here, we addressed the role of the cerebral vasculature in the passage of T. gondii to the brain parenchyma. Shortly after inoculation in mice, parasites mainly localized to cortical capillaries, in preference over post-capillary venules, cortical arterioles or meningeal and choroidal vessels. Early invasion to the parenchyma (days 1-5) occurred in absence of a measurable increase in blood-brain barrier (BBB) permeability, perivascular leukocyte cuffs or hemorrhage. However, sparse focalized permeability elevations were detected adjacently to replicative parasite foci. Further, T. gondii triggered inflammatory responses in cortical microvessels and endothelium. Pro- and anti-inflammatory treatments of mice with LPS and hydrocortisone, respectively, impacted BBB permeability and parasite loads in the brain parenchyma. Finally, pharmacological inhibition or Cre/loxP conditional knockout of endothelial focal adhesion kinase (FAK), a BBB intercellular junction regulator, facilitated parasite translocation to the brain parenchyma. The data reveal that the initial passage of T. gondii to the central nervous system occurs principally across cortical capillaries. The integrity of the microvascular BBB restricts parasite transit, which conversely is exacerbated by the inflammatory response.

scholarly journals The blood–brain barrier

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.

scholarly journals Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

2019 ◽  
Vol 87 (1) ◽  
pp. 6 ◽  
Author(s):  
Luca Bors ◽  
Franciska Erdő
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
New Technologies ◽  
Brain Barrier ◽  
Therapeutic Drug ◽  
Blood Brain ◽  
Drug Concentrations ◽  
The Brain

Treatment of certain central nervous system disorders, including different types of cerebral malignancies, is limited by traditional oral or systemic administrations of therapeutic drugs due to possible serious side effects and/or lack of the brain penetration and, therefore, the efficacy of the drugs is diminished. During the last decade, several new technologies were developed to overcome barrier properties of cerebral capillaries. This review gives a short overview of the structural elements and anatomical features of the blood–brain barrier. The various in vitro (static and dynamic), in vivo (microdialysis), and in situ (brain perfusion) blood–brain barrier models are also presented. The drug formulations and administration options to deliver molecules effectively to the central nervous system (CNS) are presented. Nanocarriers, nanoparticles (lipid, polymeric, magnetic, gold, and carbon based nanoparticles, dendrimers, etc.), viral and peptid vectors and shuttles, sonoporation and microbubbles are briefly shown. The modulation of receptors and efflux transporters in the cell membrane can also be an effective approach to enhance brain exposure to therapeutic compounds. Intranasal administration is a noninvasive delivery route to bypass the blood–brain barrier, while direct brain administration is an invasive mode to target the brain region with therapeutic drug concentrations locally. Nowadays, both technological and mechanistic tools are available to assist in overcoming the blood–brain barrier. With these techniques more effective and even safer drugs can be developed for the treatment of devastating brain disorders.

scholarly journals Function of Connexins in the Interaction between Glial and Vascular Cells in the Central Nervous System and Related Neurological Diseases

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Yinan Zhao ◽  
Yanguo Xin ◽  
Zhiyi He ◽  
Wenyu Hu
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
The Central Nervous System ◽  
Junction Proteins

Neuronal signaling together with synapse activity in the central nervous system requires a precisely regulated microenvironment. Recently, the blood-brain barrier is considered as a “neuro-glia-vascular unit,” a structural and functional compound composed of capillary endothelial cells, glial cells, pericytes, and neurons, which plays a pivotal role in maintaining the balance of the microenvironment in and out of the brain. Tight junctions and adherens junctions, which function as barriers of the blood-brain barrier, are two well-known kinds in the endothelial cell junctions. In this review, we focus on the less-concerned contribution of gap junction proteins, connexins in blood-brain barrier integrity under physio-/pathology conditions. In the neuro-glia-vascular unit, connexins are expressed in the capillary endothelial cells and prominent in astrocyte endfeet around and associated with maturation and function of the blood-brain barrier through a unique signaling pathway and an interaction with tight junction proteins. Connexin hemichannels and connexin gap junction channels contribute to the physiological or pathological progress of the blood-brain barrier; in addition, the interaction with other cell-cell-adhesive proteins is also associated with the maintenance of the blood-brain barrier. Lastly, we explore the connexins and connexin channels involved in the blood-brain barrier in neurological diseases and any programme for drug discovery or delivery to target or avoid the blood-brain barrier.

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