scholarly journals Potent and lasting seizure suppression by systemic delivery of antagomirs targeting miR-134 timed with blood-brain barrier disruption

2019 ◽  
Author(s):  
C. R. Reschke ◽  
L. F. A. Silva ◽  
V. R. Vangoor ◽  
M. Rosso ◽  
B. David ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Blood Brain Barrier ◽  
Serum Proteins ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Systemic Delivery ◽  
Systemic Injection ◽  
Blood Brain ◽  
Disease Modifying ◽  
The Brain

AbstractRNA therapies such as oligonucleotides (OGNs) offer precision treatments for a variety of neurological diseases, including epilepsy but their deployment is hampered by the blood brain barrier (BBB). Here we used brain imaging and assays of serum proteins and tracer extravasation, to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically-injected antisense OGNs targeting microRNA-134 (Ant-134) into the brain parenchyma. A single intraperitoneal injection of Ant-134 two hours after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at three months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces disease-modifying effects after systemic injection in mice when timed with BBB disruption and may be a clinically-viable approach for this and other disease-modifying microRNA therapies.

scholarly journals Nose-to-Brain Delivery

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 138 ◽  
Author(s):  
Paolo Giunchedi ◽  
Elisabetta Gavini ◽  
Maria Cristina Bonferoni
Keyword(s):  
Side Effects ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Systemic Administration ◽  
Brain Barrier ◽  
Brain Delivery ◽  
Special Issue ◽  
Drug Bioavailability ◽  
Blood Brain ◽  
The Brain

Nose-to-brain delivery represents a big challenge. In fact there is a large number of neurological diseases that require therapies in which the drug must reach the brain, avoiding the difficulties due to the blood–brain barrier (BBB) and the problems connected with systemic administration, such as drug bioavailability and side-effects. For these reasons the development of nasal formulations able to deliver the drug directly into the brain is of increasing importance. This Editorial regards the contributions present in the Special Issue “Nose-to-Brain Delivery”.

scholarly journals Neurological Diseases in Relation to the Blood–Brain Barrier

2012 ◽  
Vol 32 (7) ◽  
pp. 1139-1151 ◽  
Author(s):  
Gary A Rosenberg
Keyword(s):  
Free Radicals ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Neurovascular Unit ◽  
Brain Barrier ◽  
Cellular Damage ◽  
Brain Diseases ◽  
Acute Injury ◽  
Blood Brain ◽  
The Brain

Disruption of the blood–brain barrier (BBB) has an important part in cellular damage in neurological diseases, including acute and chronic cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, and brain infections. The neurovascular unit (NVU) forms the interface between the blood and brain tissues. During an injury, the cascade of molecular events ends in the final common pathway for BBB disruption by free radicals and proteases, which attack membranes and degrade the tight junction proteins in endothelial cells. Free radicals of oxygen and nitrogen and the proteases, matrix metalloproteinases and cyclooxgyenases, are important in the early and delayed BBB disruption as the neuroinflammatory response progresses. Opening of the BBB occurs in neurodegenerative diseases and contributes to the cognitive changes. In addition to the importance of the NVU in acute injury, angiogenesis contributes to the recovery process. The challenges to treatment of the brain diseases involve not only facilitating drug entry into the brain, but also understanding the timing of the molecular cascades to block the early NVU injury without interfering with recovery. This review will describe the molecular and cellular events associated with NVU disruption and potential strategies directed toward restoring its integrity.

scholarly journals From Blood to the Brain: Can Systemically Transplanted Mesenchymal Stem Cells Cross the Blood-Brain Barrier?

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Linan Liu ◽  
Mark A. Eckert ◽  
Hamidreza Riazifar ◽  
Dong-Ku Kang ◽  
Dritan Agalliu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Inflammatory Diseases ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Therapeutic Effects ◽  
Blood Brain ◽  
The Brain

Systemically infused mesenchymal stem cells (MSCs) are emerging therapeutics for treating stroke, acute injuries, and inflammatory diseases of the central nervous system (CNS), as well as brain tumors due to their regenerative capacity and ability to secrete trophic, immune modulatory, or other engineered therapeutic factors. It is hypothesized that transplanted MSCs home to and engraft at ischemic and injured sites in the brain in order to exert their therapeutic effects. However, whether MSCs possess the ability to migrate across the blood-brain barrier (BBB) that separates the blood from the brain remains unresolved. This review analyzes recent advances in this area in an attempt to elucidate whether systemically infused MSCs are able to actively transmigrate across the CNS endothelium, particularly under conditions of injury or stroke. Understanding the fate of transplanted MSCs and their CNS trafficking mechanisms will facilitate the development of more effective stem-cell-based therapeutics and drug delivery systems to treat neurological diseases and brain tumors.

scholarly journals Blood-Brain Barrier Therapeutics for Neurological Diseases

2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Aarushi Sahni ◽  
Nicole Katchur
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Neuroinflammatory Response ◽  
Selective Filter ◽  
Blood Brain ◽  
The Brain

The Blood-Brain Barrier (BBB) is a highly selective filter responsible for allowing certain gases such as oxygen and lipid-soluble molecules to pass (Anand 2014). Its selectiveness makes it challenging for many therapeutics to combat Alzheimer’s and Parkinson’s disease with external drug therapies. Large-molecule drug therapies never pass the BBB while small-molecule drugs pass only about 5% of the time (Pardridge 2005). In Alzheimer’s disease, tight junctions between endothelial cells degrade, causing an unregulated accumulation of amyloid-β (Aβ) protein (Ramanathan 2015). Consequently, this leads to the formation of neurofibrillary tangles that cut off the nutrient supply to the brain cells and kill neurons (Ramanathan 2015). In Parkinson’s disease, astrocyte mutations cause a build-up of α-synuclein (αSyn) which affects the neuroinflammatory response and causes dysfunction in dopaminergic neurons (Booth 2017; Meade 2019). New drug therapies for Alzheimer’s and Parkinson’s continue to undergo trials; some such as FPS-ZM1 and tilavonemab for Alzheimer’s and Ravicti for Parkinson’s have shown promising results. In addition, similarities in dysfunction for both diseases and some types of cancer have sparked possibilities in retargeting cancer drugs to improve Alzheimer's and Parkinson’s pathologies. This review will summarize current therapeutic advancements for Alzheimer’s and Parkinson’s disease and their possible future contributions.

The blood–brain barrier and its regulation by NF-κB

e-Neuroforum ◽  
2016 ◽  
Vol 22 (2) ◽  
Author(s):  
J. Wenzel ◽  
M. Schwaninger
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Serum Proteins ◽  
Hereditary Disease ◽  
Brain Barrier ◽  
Incontinentia Pigmenti ◽  
Brain Endothelial Cells ◽  
Blood Brain ◽  
Endothelial Cell Death ◽  
The Brain

AbstractThe brain is protected by a tight barrier between the blood and parenchyma. This so-called blood-brain barrier protects the brain from invading pathogens, infiltrating immune cells, and the extravasation of serum proteins. Beside pericytes and astrocytes mainly endothelial cells form this barrier.Inflammation leads to an increase in the permeability of the blood-brain barrier. NF-κB is activated during inflammation and is a key regulator of inflammatory processes. In brain endothelial cells NF-κB protects the blood-brain barrier. Loss of the NF-κB activating protein NEMO in brain endothelial cells leads to endothelial cell death, increased permeability, and epilepsy inmice as well as in humans with the hereditary disease incontinentia pigmenti. Therefore, inflammatory mediators are able to disturb but also to protect the blood-brain barrier.

Radioactively iodinated cyclo(His-Pro) crosses the blood-brain barrier and reverses ethanol-induced narcosis

1993 ◽  
Vol 264 (5) ◽  
pp. E723-E729 ◽  
Author(s):  
W. A. Banks ◽  
A. J. Kastin ◽  
V. Akerstrom ◽  
J. B. Jaspan
Keyword(s):  
Blood Brain Barrier ◽  
Serum Proteins ◽  
Intraperitoneal Administration ◽  
Brain Barrier ◽  
Lipid Solubility ◽  
Peripheral Tissues ◽  
Blood Brain ◽  
Other Substances ◽  
High Lipid Solubility ◽  
The Brain

Cyclo(His-Pro) (cHP) is a peptide widely distributed in the central nervous system (CNS) and peripheral tissues that can affect brain function after either peripheral or CNS administration. This suggests that cHP may be a neuromodulator capable of crossing the blood-brain barrier (BBB). We, therefore, studied the ability of radioactively labeled cHP (I-cHP) to cross the BBB. We found that I-cHP can cross the BBB in either the direction of blood to brain or brain to blood by nonsaturable mechanisms. The rate of entry of I-cHP into the CNS was low in comparison with other peptides, especially considering its relatively low molecular weight and high lipid solubility. However, this slow entry was offset by a long half-life in blood and extreme enzymatic resistance, allowing cHP to accumulate in the CNS. This accumulation was sufficient to allow intravenous cHP to reverse ethanol-induced narcosis, an effect mediated through the CNS. The rate of entry of I-cHP was resistant to conditions that alter the passage of some other substances across the BBB or that have been shown to affect cHP metabolism such as aging, diabetes, and pretreatment with aluminum. Entry of cHP into the brain was not retarded by binding to serum proteins. Significant amounts of I-cHP entered the serum, brain, and other tissues after intraperitoneal administration, the route used in many studies of cHP. Taken together, these results show that cHP is a highly stable peptide that, after intravenous injection, slowly enters the brain by a nonsaturable mechanism in amounts large enough to affect such aspects of the CNS as ethanol-induced narcosis.

scholarly journals Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

2021 ◽  
Vol 22 (14) ◽  
pp. 7710
Author(s):  
Ying-Chieh Wu ◽  
Tuuli-Maria Sonninen ◽  
Sanni Peltonen ◽  
Jari Koistinaho ◽  
Šárka Lehtonen
Keyword(s):  
Stem Cell ◽  
Neurodegenerative Diseases ◽  
Blood Brain Barrier ◽  
Current Knowledge ◽  
Neurological Diseases ◽  
Induced Pluripotent Stem Cell ◽  
Brain Barrier ◽  
Blood Brain ◽  
Induced Pluripotent ◽  
The Brain

The blood–brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer’s disease and Parkinson’s disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.

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.

scholarly journals Transportation of Single-Domain Antibodies through the Blood–Brain Barrier

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1131
Author(s):  
Eduardo Ruiz-López ◽  
Alberto J. Schuhmacher
Keyword(s):  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Cell Penetrating Peptides ◽  
Brain Parenchyma ◽  
Single Domain ◽  
Brain Barrier ◽  
Antigen Specificity ◽  
Blood Brain ◽  
Single Domain Antibodies ◽  
The Brain

Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. Nevertheless, numerous neurological diseases and brain pathologies, including cancer, result in BBB leakiness favoring single-domain antibodies uptake into the CNS. Some single-domain antibodies have been reported to naturally cross the BBB. In addition, different strategies and methods to deliver both nanobodies and VNARs into the brain parenchyma can be exploited when the BBB is intact. These include device-based and physicochemical disruption of the BBB, receptor and adsorptive-mediated transcytosis, somatic gene transfer, and the use of carriers/shuttles such as cell-penetrating peptides, liposomes, extracellular vesicles, and nanoparticles. Approaches based on single-domain antibodies are reaching the clinic for other diseases. Several tailoring methods can be followed to favor the transport of nanobodies and VNARs to the CNS, avoiding the limitations imposed by the BBB to fulfill their therapeutic, diagnostic, and theragnostic promises for the benefit of patients suffering from CNS pathologies.

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.

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