scholarly journals Sphenopalatine Ganglion Stimulation Upregulates Transport of Temozolomide across the Blood-Brain Barrier

2020 ◽  
Vol 88 (3) ◽  
pp. 40
Author(s):  
Thana N. Theofanis ◽  
Ankit K. Rochani ◽  
Richard F. Schmidt ◽  
Michael J. Lang ◽  
Geoffrey P. Stricsek ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Therapeutic Potential ◽  
Low Frequency ◽  
The United States ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Target Tissue ◽  
Sphenopalatine Ganglion ◽  
Blood Brain ◽  
Treatment Paradigm

Sphenopalatine ganglion (SPG) stimulation has been shown to reversibly alter blood-brain barrier (BBB) permeability. It is widely used for the treatment of cluster headaches in Europe and is well tolerated in humans. The therapeutic potential for SPG stimulation in other central nervous system (CNS) diseases has yet to be explored. Glioblastoma Multiforme (GBM) remains one of the most difficult primary CNS neoplasms to treat, with an average survival of approximately 18 months at the time of diagnosis. Since 2004, the gold standard of treatment for GBM in the United States includes surgery followed by treatment with temozolomide (TMZ) and radiation. We sought to determine if SPG stimulation could increase chemotherapy concentrations in rodent brains with an intact BBB. Here, we show a statistically significant (p = 0.0006), five-fold upregulation of TMZ crossing the BBB and reaching brain parenchyma in rats receiving low-frequency (LF, 10 Hz) SPG stimulation. All the measurements were performed using a highly sensitive liquid chromatography mass spectrometry (LCMS) method that was developed for quantitation of TMZ in plasma and brain tissue. Our treatment paradigm shows novel delivery route by which we could more effectively and safely deliver TMZ in a targeted manner, to minimize systemic toxicity and maximize action at the target tissue.

scholarly journals Sphenopalatine Ganglion Stimulation Upregulates Transport of Intra-Arterial Temozolomide Across the Blood–Brain Barrier

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Thana N Theofanis ◽  
Ankit Rochani ◽  
Richard F Schmidt ◽  
Michael J Lang ◽  
Geoffrey Stricsek ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
High Performance ◽  
Internal Standard ◽  
The United States ◽  
Rat Plasma ◽  
Brain Barrier ◽  
Target Tissue ◽  
Sphenopalatine Ganglion ◽  
Blood Brain ◽  
Treatment Paradigm

Abstract INTRODUCTION Sphenopalatine ganglion (SPG) stimulation has been shown to reversibly alter blood–brain barrier (BBB) permeability. At the present time, it is widely used for the treatment of cluster headaches in Europe and is well tolerated for this use in humans. METHODS In a rat model, we assessed the permeability of intra-arterial temozolomide with and without sphenopalatine ganglion stimulation. We developed a high-performance liquid chromatography and mass spectrometry method to measure temozolomide in rat plasma and brain tissue, with caffeine as the internal standard. RESULTS Here we show a statistically significant (P = .0006), 5-fold upregulation of TMZ crossing the BBB and reaching brain parenchyma in rats receiving low-frequency (LF, 10 Hz) SPG stimulation. CONCLUSION Glioblastoma multiforme (GBM) remains an extremely difficult disease to treat. Since 2004, the gold standard of treatment for GBM in the United States includes surgery + TMZ and radiation. Our treatment paradigm shows a mechanism in which we could more effectively and safely deliver TMZ in a targeted manner, to minimize systemic toxicity and maximize action at the target tissue. The SPG Stimulation treatment paradigm could be used in a broad spectrum of central nervous system (CNS) pathologies.

scholarly journals Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction

2020 ◽  
Vol 11 ◽  
Author(s):  
Keqing Nian ◽  
Ian C. Harding ◽  
Ira M. Herman ◽  
Eno E. Ebong
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Neurovascular Unit ◽  
The United States ◽  
Brain Barrier ◽  
Endothelial Glycocalyx ◽  
Altered Expression ◽  
Blood Brain

Ischemic stroke, a major cause of mortality in the United States, often contributes to disruption of the blood-brain barrier (BBB). The BBB along with its supportive cells, collectively referred to as the “neurovascular unit,” is the brain’s multicellular microvasculature that bi-directionally regulates the transport of blood, ions, oxygen, and cells from the circulation into the brain. It is thus vital for the maintenance of central nervous system homeostasis. BBB disruption, which is associated with the altered expression of tight junction proteins and BBB transporters, is believed to exacerbate brain injury caused by ischemic stroke and limits the therapeutic potential of current clinical therapies, such as recombinant tissue plasminogen activator. Accumulating evidence suggests that endothelial mechanobiology, the conversion of mechanical forces into biochemical signals, helps regulate function of the peripheral vasculature and may similarly maintain BBB integrity. For example, the endothelial glycocalyx (GCX), a glycoprotein-proteoglycan layer extending into the lumen of bloods vessel, is abundantly expressed on endothelial cells of the BBB and has been shown to regulate BBB permeability. In this review, we will focus on our understanding of the mechanisms underlying BBB damage after ischemic stroke, highlighting current and potential future novel pharmacological strategies for BBB protection and recovery. Finally, we will address the current knowledge of endothelial mechanotransduction in BBB maintenance, specifically focusing on a potential role of the endothelial GCX.

scholarly journals The Potential Roles of Blood–Brain Barrier and Blood–Cerebrospinal Fluid Barrier in Maintaining Brain Manganese Homeostasis

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1833
Author(s):  
Shannon Morgan McCabe ◽  
Ningning Zhao
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Blood Circulation ◽  
Critical Role ◽  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a “privileged” organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood–brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood–CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.

IMMUNOHISTOCHEMICAL STUDIES OF BLOOD BRAIN BARRIER AFTER ADMINISTRATION OF ABHRAK BHASM IN WISTAR RATS

2021 ◽  
pp. 13-19
Author(s):  
Amita Singh ◽  
Raj Kumar ◽  
S. K. Kannaujia ◽  
Manikrishna Manikrishna ◽  
N. P. Singh
Keyword(s):  
Blood Brain Barrier ◽  
Wistar Rats ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Major Constituent ◽  
Control Group ◽  
Blood Brain ◽  
Biological Studies ◽  
Immunohistochemical Studies ◽  
The Brain

Abhrak bhasma (AB) is a type of bhasma prepared from repeated incineration of mineral mica with decoctions of about 72 herbs. The particle size of Abhrak bhasm has been shown to be in the range of 29-88 nanometers and Fe, Ca, Si, Mg and K are found to be as major constituent. Many drugs developed to treat Central Nervous System (CNS) disorders are unable to reach the brain parenchyma in therapeutically relevant concentrations. The blood brain barrier protects brain parenchyma from the uctuation of plasma composition, from pathogenic agents and maintains homeostasis of the brain parenchyma by restricting non-specic ux of ions, peptides, proteins and even cells into and out the brain. Immunohistochemistry is being widely employed as a tool for biological studies. This study is conducted to examine the change in the continuity of Blood brain barrier by using immunohistochemistry, once Abhrak bhasm drug is given in experimental animal and also to examine the histology of organs. In this study a total of 30 adult albino Wistar rats of approximately 4 months age (approx. 150-200 gms) of either sex selected randomly to see the effect of Abhrak bhasm, an ayurvedic drug on Wistar rats. The rats were weighed, marked and divided into 5 groups each consisting of six animals. In normal control group (Group E), no drug was administered and in rest of the four treated groups (Group-A,B,C,D), Abhrak bhasm @ 36 mg/kg B.wt. was administered orally once in each rat. Brain, liver, kidneys,spleen and blood samples were collected in 10% formalin solution after euthanizing the rats at 0.5,2,6 & 12 hours of Abhrak bhasma drug intervention. The alterations in any of the biochemical parameters are within the tolerable limits of liver and kidney since the dose of abhrak bhasm did not affect liver and kidneys. In the present study, the increase in ALP level may be the result of alterations in metabolisms that occurred without any signicant alteration in histology of liver. After applying the immunohistochemistry with the research markers GFAP, CD 34, S 100, GLUT-1 and RECA-1 on the rats in groups A,B,C and D, there was no change in the intensity of immunohistochemistry, with respect to control. While on applying the Occludin, the intensity of immunohistochemistry was reduced in all the treatment groups as compared to the control group. On the basis of ndings of present study it can be concluded that the therapeutic dose of Abhrak bhasma causes changes at the level of tight junctions present in blood brain barrier in rats which is shown by immunohistochemistry with occludin research marker. There is no toxic effect of drug on different organs of rats as no signicant changes in histology of organs are seen. More studies need to be done to check the permeability of blood brain barrier for Abhrak bhasma drug, like calculating its concentration in brain tissues and other vital organs of rat.

scholarly journals Dendrimeric Poly(Epsilon-Lysine) Delivery Systems for the Enhanced Permeability of Flurbiprofen across the Blood-Brain Barrier in Alzheimer’s Disease

2018 ◽  
Vol 19 (10) ◽  
pp. 3224 ◽  
Author(s):  
Shafq Al-azzawi ◽  
Dhafir Masheta ◽  
Anna Guildford ◽  
Gary Phillips ◽  
Matteo Santin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Solid Phase ◽  
Synthesis Method ◽  
Delivery Systems ◽  
Brain Barrier ◽  
Target Cells ◽  
Target Tissue ◽  
Blood Brain

Alzheimer’s disease (AD) is a progressive brain disorder and age-related disease characterised by abnormal accumulation of β-amyloid (Aβ). The development of drugs to combat AD is hampered by the lack of therapeutically-active molecules able to cross the blood-brain barrier (BBB). It is agreed that specifically-designed carriers, such as dendrimers, could support the drug penetration across the BBB. The aim of this study was to design biocompatible and biodegradable dendrimeric delivery systems able to carry Flurbiprofen (FP), as drug for AD treatment, across the BBB and liberate it at the target tissue. These dendrons were synthesised using solid-phase peptide synthesis method and characterised by mass spectrometry and fourier-transform infrared spectroscopy (FTIR). The results revealed successful synthesis of dendrons having FP been integrated during the synthesis at their branching ends. Cytotoxicity assays demonstrated the biocompatibility of the delivery systems, whereas HPLC analysis showed high percentages of permeability across an in vitro BBB model for FP-integrated dendrons. Results also revealed the efficiency of drug conjugates on the γ-secretase enzyme in target cells with evidence of eventual drug release by hydrolysis of the carrier. This study demonstrates that the coupling of FP to dendrimeric delivery systems can successfully be achieved during the synthesis of the poly(epsilon-lysine) macromolecules to improve the transport of the active drug across the BBB.

scholarly journals Targeting microRNAs to Regulate the Integrity of the Blood–Brain Barrier

2021 ◽  
Vol 9 ◽  
Author(s):  
Juntao Wang ◽  
Fang Xu ◽  
Xiaoming Zhu ◽  
Xianghua Li ◽  
Yankun Li ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Cerebrovascular Diseases ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Blood Brain ◽  
Recent Developments ◽  
Important Regulator

The blood–brain barrier (BBB) is a highly specialized neurovascular unit that protects the brain from potentially harmful substances. In addition, the BBB also engages in the exchange of essential nutrients between the vasculature and brain parenchyma, which is critical for brain homeostasis. Brain diseases, including neurological disorders and cerebrovascular diseases, are often associated with disrupted BBB integrity, evidenced by increased permeability. Therefore, defining the mechanisms underlying the regulation of BBB integrity is crucial for the development of novel therapeutics targeting brain diseases. MicroRNAs (miRNA), a type of small non-coding RNAs, are emerging as an important regulator of BBB integrity. Here we review recent developments related to the role of miRNAs in regulating BBB integrity.

scholarly journals In vitro models of the blood–brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use

2016 ◽  
Vol 36 (5) ◽  
pp. 862-890 ◽  
Author(s):  
Hans C Helms ◽  
N Joan Abbott ◽  
Malgorzata Burek ◽  
Romeo Cecchelli ◽  
Pierre-Olivier Couraud ◽  
...  
Keyword(s):  
Cell Culture ◽  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
Culture Models ◽  
Cell Culture Models ◽  
The Brain

The endothelial cells lining the brain capillaries separate the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic components of plasma and xenobiotics. This “blood-brain barrier” function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug transport to the brain and studies of endothelial cell biology and pathophysiology. In this review, we aim to give an overview of established in vitro blood–brain barrier models with a focus on their validation regarding a set of well-established blood–brain barrier characteristics. As an ideal cell culture model of the blood–brain barrier is yet to be developed, we also aim to give an overview of the advantages and drawbacks of the different models described.

scholarly journals Penetration of the blood-brain barrier: enhancement of drug delivery and imaging by bacterial glycopeptides.

1995 ◽  
Vol 182 (4) ◽  
pp. 1037-1043 ◽  
Author(s):  
B Spellerberg ◽  
S Prasad ◽  
C Cabellos ◽  
M Burroughs ◽  
P Cahill ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Pharmacological Agents ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
The Brain

The blood-brain barrier restricts the passage of many pharmacological agents into the brain parenchyma. Bacterial glycopeptides induce enhanced blood-brain barrier permeability when they are present in the subarachnoid space during meningitis. By presenting such glycopeptides intravenously, blood-brain barrier permeability in rabbits was enhanced in a reversible time- and dose-dependent manner to agents < or = 20 kD in size. Therapeutic application of this bioactivity was evident as enhanced penetration of the antibiotic penicillin and the magnetic resonance imaging contrast agent gadolinium-diethylene-triamine-pentaacetic acid into the brain parenchyma.

scholarly journals PET-MRI nanoparticles imaging of blood–brain barrier damage and modulation after stroke reperfusion

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Justine Debatisse ◽  
Omer Faruk Eker ◽  
Océane Wateau ◽  
Tae-Hee Cho ◽  
Marlène Wiart ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Ischaemic Stroke ◽  
Blood Brain Barrier ◽  
Acute Ischaemic Stroke ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Resonance Imaging ◽  
Blood Brain ◽  
Blood Brain Barrier Damage

Abstract In an acute ischaemic stroke, understanding the dynamics of blood–brain barrier injury is of particular importance for the prevention of symptomatic haemorrhagic transformation. However, the available techniques assessing blood–brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood–brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood–brain barrier damage and refine the delivery of neuroprotective agents. We previously developed an original endovascular stroke model of acute ischaemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (<1 nm) and AGuIX® nanoparticles (∼5 nm) used for brain theranostics. On dynamic contrast-enhanced magnetic resonance imaging, the baseline transfer constant Ktrans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] ×10−3 min−1, respectively, in the normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] ×10−3 min−1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, Ktrans for both Gd-DOTA and AGuIX® nanoparticles was significantly higher within the ischaemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] ×10−3 min−1 for Gd-DOTA and AGuIX® nanoparticles, respectively. With AGuIX® nanoparticles, Ktrans also increased within the ischaemic growth areas, suggesting added value for AGuIX®. Finally, Ktrans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n = 7) compared to placebo (n = 5). Ktrans quantification with AGuIX® nanoparticles can monitor early blood–brain barrier damage and treatment effect in ischaemic stroke after reperfusion.

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