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 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 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.

High performance collection of cerebrospinal fluid in rats: Evaluation of erythropoietin penetration after osmotic opening of the blood–brain barrier

2013 ◽  
Vol 219 (1) ◽  
pp. 70-75 ◽  
Author(s):  
Natalia Ceaglio ◽  
Gustavo Orozco ◽  
Marina Etcheverrigaray ◽  
Mónica Mattio ◽  
Ricardo Kratje ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
High Performance ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

2019 ◽  
Vol 11 ◽  
pp. 117957351984065 ◽  
Author(s):  
Divine C Nwafor ◽  
Allison L Brichacek ◽  
Afroz S Mohammad ◽  
Jessica Griffith ◽  
Brandon P Lucke-Wold ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Blood Brain Barrier ◽  
Immune Cell ◽  
The United States ◽  
Brain Barrier ◽  
Blood Brain ◽  
Systemic Inflammatory Disease ◽  
Sepsis Survivors ◽  
The Brain

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors.

scholarly journals Mechanisms of Blood–Brain Barrier Dysfunction in Traumatic Brain Injury

2020 ◽  
Vol 21 (9) ◽  
pp. 3344 ◽  
Author(s):  
Alison Cash ◽  
Michelle H. Theus
Keyword(s):  
Blood Brain Barrier ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Brain Injuries ◽  
The United States ◽  
Brain Barrier ◽  
Detection Methods ◽  
Secondary Injury ◽  
Barrier Dysfunction ◽  
Blood Brain

Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation into the secondary injury is necessary in order to formulate an effective treatment. A mechanical consequence of trauma involves dysregulation of the blood–brain barrier (BBB) which contributes to secondary injury and exposure of peripheral components to the brain parenchyma. Recent studies have shed light on the mechanisms of BBB breakdown in TBI including novel intracellular signaling and cell–cell interactions within the BBB niche. The current review provides an overview of the BBB, novel detection methods for disruption, and the cellular and molecular mechanisms implicated in regulating its stability following TBI.

scholarly journals Population pharmacokinetic approach for evaluation of treosulfan and its active monoepoxide disposition in plasma and brain on the basis of a rat model

2020 ◽  
Vol 72 (5) ◽  
pp. 1297-1309
Author(s):  
Dorota Danielak ◽  
Michał Romański ◽  
Anna Kasprzyk ◽  
Artur Teżyk ◽  
Franciszek Główka
Keyword(s):  
Blood Brain Barrier ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Estimation Method ◽  
Rat Plasma ◽  
Brain Barrier ◽  
Male Rats ◽  
Population Pharmacokinetic ◽  
Blood Brain ◽  
The Brain

Abstract Purpose Efficacy of treosulfan, used in the treatment of marrow disorders, depends on the activity of its monoepoxy—(EBDM) and diepoxy compounds. The study aimed to describe the pharmacokinetics of treosulfan and EBDM in the rat plasma and brain by means of mixed-effects modelling. Methods The study had a one-animal-per-sample design and included ninty-six 10-week-old Wistar rats of both sexes. Treosulfan and EBDM concentrations in the brain and plasma were measured by an HPLC–MS/MS method. The population pharmacokinetic model was established in NONMEM software with a first-order estimation method with interaction. Results One-compartment pharmacokinetic model best described changes in the concentrations of treosulfan in plasma, and EBDM concentrations in plasma and in the brain. Treosulfan concentrations in the brain followed a two-compartment model. Both treosulfan and EBDM poorly penetrated the blood–brain barrier (ratio of influx and efflux clearances through the blood–brain barrier was 0.120 and 0.317 for treosulfan and EBDM, respectively). Treosulfan plasma clearance was significantly lower in male rats than in females (0.273 L/h/kg vs 0.419 L/h/kg). Conclusions The developed population pharmacokinetic model is the first that allows the prediction of treosulfan and EBDM concentrations in rat plasma and brain. These results provide directions for future studies on treosulfan regarding the contribution of transport proteins or the development of a physiological-based model.

Sphenopalatine ganglion stimulation is a reversible and frequency-dependent modulator of the blood-brain barrier

2019 ◽  
Vol 1718 ◽  
pp. 231-241 ◽  
Author(s):  
Richard F. Schmidt ◽  
Thana N. Theofanis ◽  
Michael J. Lang ◽  
Geoffrey P. Stricsek ◽  
Ruihe Lin ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Sphenopalatine Ganglion ◽  
Frequency Dependent ◽  
Blood Brain

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.

Solving the challenge of the blood–brain barrier to treat infections caused by Trypanosoma evansi: evaluation of nerolidol-loaded nanospheres in mice

Parasitology ◽  
2017 ◽  
Vol 144 (11) ◽  
pp. 1543-1550 ◽  
Author(s):  
MATHEUS D. BALDISSERA ◽  
CARINE F. SOUZA ◽  
ALINE A. BOLIGON ◽  
THIRSSA H. GRANDO ◽  
MARIÂNGELA F. DE SÁ ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Blood Brain Barrier ◽  
High Performance ◽  
Drug Efficacy ◽  
Trypanosoma Evansi ◽  
Brain Barrier ◽  
Active Principle ◽  
Diminazene Aceturate ◽  
Blood Brain ◽  
The Brain

SUMMARYDespite significant advances in therapies against Trypanosoma evansi, its effective elimination from the central nervous system (CNS) remains a difficult task. The incapacity of trypanocidal drugs to cross the blood–brain barrier (BBB) after systemic administrations makes the brain the main refuge area for T. evansi. Nanotechnology is showing great potential to improve drug efficacy, such as nerolidol-loaded nanospheres (N-NS). Thus, the aim of this study was to investigate whether the treatment with N-NS was able to cross the BBB and to eliminate T. evansi from the CNS. High-performance liquid chromatography revealed that N-NS can cross the BBB of T. evansi-infected mice, while free nerolidol (F-N) neither the trypanocidal drug diminazene aceturate (D.A.) were not detected in the brain tissue. Polymerase chain reaction revealed that 100% of the animals treated with N-NS were negatives for T. evansi in the brain tissue, while all infected animals treated with F-N or D.A. were positives. Thus, we concluded that nanotechnology improves the therapeutic efficacy of nerolidol, and enables the transport of its active principle through the BBB. In summary, N-NS treatment can eliminate the parasite from the CNS, and possesses potential to treat infected animals.

Sign in / Sign up

Export Citation Format

Share Document