scholarly journals Photodynamic Opening of the Blood–Brain Barrier Using Different Photosensitizers in Mice

2019 ◽  
Vol 10 (1) ◽  
pp. 33 ◽  
Author(s):  
Oxana Semyachkina-Glushkovskaya ◽  
Ekaterina Borisova ◽  
Vanya Mantareva ◽  
Ivan Angelov ◽  
Ivelina Eneva ◽  
...  
Keyword(s):  
Tight Junction ◽  
Blood Brain Barrier ◽  
Confocal Imaging ◽  
Brain Barrier ◽  
Zinc Phthalocyanine ◽  
Brain Diseases ◽  
Blood Brain ◽  
Age Related ◽  
Dextran 70 ◽  
The Brain

In a series of previous studies, we demonstrated that the photodynamic therapy (PDT), as a widely used tool for treatment of glioblastoma multiforme (GBM), also site-specifically opens the blood–brain barrier (BBB) in PDT-dose and age-related manner via reversible disorganization of the tight junction machinery. To develop the effective protocol of PDT-opening of the BBB, here we answer the question of what kind of photosensitizer (PS) is the most effective for the BBB opening. We studied the PDT-opening of the BBB in healthy mice using commercial photosensitizers (PSs) such as 5-aminolevulenic acid (5-ALA), aluminum phthalocyanine disulfonate (AlPcS), zinc phthalocyanine (ZnPc) and new synthetized PSs such as galactose functionalized ZnPc (GalZnPc). The spectrofluorimetric assay of Evans Blue albumin complex (EBAC) leakage and 3-D confocal imaging of FITC-dextran 70 kDa (FITCD) extravasation clearly shows a revisable and dose depended PDT-opening of the BBB to EBAC and FITCD associated with a decrease in presence of tight junction (TJ) in the vascular endothelium. The PDT effects on the BBB permeability, TJ expression and the fluorescent signal from the brain tissues are more pronounced in PDT-GalZnPc vs. PDT-5-ALA/AlPcS/ZnPc. These pre-clinical data are the first important informative platform for an optimization of the PDT protocol in the light of new knowledge about PDT-opening of the BBB for drug brain delivery and for the therapy of brain diseases.

scholarly journals Probable Causes of Alzheimer’s Disease

Sci ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 16
Author(s):  
James David Adams
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lactic Acid ◽  
Blood Brain Barrier ◽  
Transient Receptor Potential ◽  
Brain Barrier ◽  
Folate Intake ◽  
Blood Brain ◽  
Age Related ◽  
The Brain

A three-part mechanism is proposed for the induction of Alzheimer’s disease: (1) decreased blood lactic acid; (2) increased blood ceramide and adipokines; (3) decreased blood folic acid. The age-related nature of these mechanisms comes from age-associated decreased muscle mass, increased visceral fat and changes in diet. This mechanism also explains why many people do not develop Alzheimer’s disease. Simple changes in lifestyle and diet can prevent Alzheimer’s disease. Alzheimer’s disease is caused by a cascade of events that culminates in damage to the blood–brain barrier and damage to neurons. The blood–brain barrier keeps toxic molecules out of the brain and retains essential molecules in the brain. Lactic acid is a nutrient to the brain and is produced by exercise. Damage to endothelial cells and pericytes by inadequate lactic acid leads to blood–brain barrier damage and brain damage. Inadequate folate intake and oxidative stress induced by activation of transient receptor potential cation channels and endothelial nitric oxide synthase damage the blood–brain barrier. NAD depletion due to inadequate intake of nicotinamide and alterations in the kynurenine pathway damages neurons. Changes in microRNA levels may be the terminal events that cause neuronal death leading to Alzheimer’s disease. A new mechanism of Alzheimer’s disease induction is presented involving lactic acid, ceramide, IL-1β, tumor necrosis factor α, folate, nicotinamide, kynurenine metabolites and microRNA.

scholarly journals Modulating the Blood-Brain Barrier by Light Stimulation of Molecular-Targeted Nanoparticles

2020 ◽  
Author(s):  
Xiaoqing Li ◽  
Vamsidhara Vemireddy ◽  
Qi Cai ◽  
Hejian Xiong ◽  
Peiyuan Kang ◽  
...  
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Therapeutic Interventions ◽  
Brain Barrier ◽  
Light Stimulation ◽  
Targeted Nanoparticles ◽  
Blood Brain ◽  
The Brain ◽  
Stimulation Of

AbstractThe blood-brain barrier (BBB) tightly regulates the entry of molecules into the brain by tight junctions that seals the paracellular space and receptor-mediated transcytosis. It remains elusive to selectively modulate these mechanisms and to overcome BBB without significant neurotoxicity. Here we report that light stimulation of tight junction-targeted plasmonic nanoparticles selectively opens up the paracellular route to allow diffusion through the compromised tight junction and into the brain parenchyma. The BBB modulation does not impair vascular dynamics and associated neurovascular coupling, or cause significant neural injury. It further allows antibody and adeno-associated virus delivery into local brain regions. This novel method offers the first evidence of selectively modulating BBB tight junctions and opens new avenues for therapeutic interventions in the central nervous system.One Sentence SummaryGentle stimulation of molecular-targeted nanoparticles selectively opens up the paracellular pathway and allows macromolecules and gene therapy vectors into the brain.

Current Updates on the Regulation of Beta-Secretase Movement as a Potential Restorative Focus for Management of Alzheimer's Disease

2019 ◽  
Vol 26 (8) ◽  
pp. 579-587 ◽  
Author(s):  
Syed Sayeed Ahmad ◽  
Mohammad Amjad Kamal
Keyword(s):  
Blood Brain Barrier ◽  
Recent Decade ◽  
High Rate ◽  
Brain Barrier ◽  
Blood Brain ◽  
Age Related ◽  
Beta Secretase ◽  
Influx Transport ◽  
Clearance Receptor ◽  
The Brain

The most recent decade was described by a developing awareness about the seriousness of dementia in the field of age-related people. Among the dementias, Alzheimer's assumes a plentiful role as a result of its amazingly high rate and casualty. A few pharmacological procedures have been attempted yet at the same time now, Alzheimer continues being an untreatable malady. The collection of Aβ in the brain is an early poisonous occasion in the pathogenesis of Alzheimer's disease, which is the most widely recognized type of dementia correlated with plaques and tangles within the brain. However, the mechanism of the intraneuronal direction of BACE1 is poorly understood. AD is caused by mutations in one of the genes that encoding APP, presenilins 1 and 2. Most of the mutations in these genes increase Aβ42 production. Numerous receptors are associated with initiating Aβ transport and clearance. Among them, RAGE is an influx transport receptor that binds soluble Aβ and mediates pathophysiological cellular responses. RAGE additionally intervenes the vehicle of plasma Aβ over the blood-brain barrier. LRP-1 functions as a clearance receptor for Aβ at the blood-brain barrier. The regulation of beta-secretase movement is being explored as a potential restorative focus for treating AD.

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 A Reevaluation of Chitosan-Decorated Nanoparticles to Cross the Blood-Brain Barrier

Membranes ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 212 ◽  
Author(s):  
Hernán Cortés ◽  
Sergio Alcalá-Alcalá ◽  
Isaac H. Caballero-Florán ◽  
Sergio A. Bernal-Chávez ◽  
Arturo Ávalos-Fuentes ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Transport Systems ◽  
Future Directions ◽  
Blood Brain ◽  
Dynamic Interface ◽  
And Function ◽  
The Brain

The blood-brain barrier (BBB) is a sophisticated and very selective dynamic interface composed of endothelial cells expressing enzymes, transport systems, and receptors that regulate the passage of nutrients, ions, oxygen, and other essential molecules to the brain, regulating its homeostasis. Moreover, the BBB performs a vital function in protecting the brain from pathogens and other dangerous agents in the blood circulation. Despite its crucial role, this barrier represents a difficult obstacle for the treatment of brain diseases because many therapeutic agents cannot cross it. Thus, different strategies based on nanoparticles have been explored in recent years. Concerning this, chitosan-decorated nanoparticles have demonstrated enormous potential for drug delivery across the BBB and treatment of Alzheimer’s disease, Parkinson’s disease, gliomas, cerebral ischemia, and schizophrenia. Our main objective was to highlight the high potential of chitosan adsorption to improve the penetrability through the BBB of nanoformulations for diseases of CNS. Therefore, we describe the BBB structure and function, as well as the routes of chitosan for crossing it. Moreover, we define the methods of decoration of nanoparticles with chitosan and provide numerous examples of their potential utilization in a variety of brain diseases. Lastly, we discuss future directions, mentioning the need for extensive characterization of proposed nanoformulations and clinical trials for evaluation of their efficacy.

Nose to Brain Drug Delivery System

2021 ◽  
pp. 335-340
Author(s):  
Gayatri D Patil ◽  
Aditya R Nikam ◽  
Paresh A. Patil ◽  
Aakash D. Sonar
Keyword(s):  
Blood Brain Barrier ◽  
Plasma Concentrations ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Post Traumatic Stress ◽  
Brain Drug Delivery ◽  
Blood Brain ◽  
Drug Concentrations ◽  
Post Traumatic ◽  
The Brain

The treatment of brain disorders is particularly challenging due to the presence of a variety of formidable obstacles to deliver drugs selectively and effectively to the brain. Blood-brain-barrier (BBB) constitutes the major obstacle to the uptake of drugs into the brain following systemic administration. An intranasal delivery provides some drugs with short channels to bypass the blood-brain barrier (BBB), especially for those with fairly low brain concentrations after a routine delivery, thus greatly enhancing the therapeutic effect on brain diseases. The nasal mucosa is nearby the brain, cerebrospinal fluid (CSF) and the drug concentrations can exceed plasma concentrations. a longer retention time at the nasal mucosal surface, penetration enhancement of the active through the nasal epithelia, and a reduction in drug metabolism in the nasal cavity. Indications where nose-to-brain products are likely to emerge first include the following: neurodegeneration, post-traumatic stress disorder, pain, and glioblastoma.

scholarly journals O19 Development of a paediatric brain PBPK model in children with and without meningitis

2019 ◽  
Vol 104 (6) ◽  
pp. e8.3-e9 ◽  
Author(s):  
LFM Verscheijden ◽  
JB Koenderink ◽  
K Allegaert ◽  
SN de Wildt ◽  
FGM Russel
Keyword(s):  
Blood Brain Barrier ◽  
Pbpk Model ◽  
Plasma Concentrations ◽  
Model Performance ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Pbpk Models ◽  
Blood Brain ◽  
Age Related ◽  
Drug Concentrations

BackgroundSeveral paediatric physiologically-based pharmacokinetic (PBPK) models have been developed that incorporate developmental changes affecting plasma drug concentrations. Disposition into cerebrospinal fluid (CSF) is also age-related and influenced by physiological factors, including CSF production rate, but also by brain diseases, such as meningitis, which are associated with impaired blood-brain barrier integrity. Our aim was to develop a paediatric brain PBPK model to predict CSF drug concentrations in children with and without meningitis.MethodsA paediatric PBPK model was developed incorporating age-appropriate parameters and associated inter-individual variability. The model was validated for paracetamol, ibuprofen, flurbiprofen and naproxen, and for a paediatric meningitis population by estimating meropenem blood-brain barrier penetration using sensitivity analysis. Plasma and CSF drug concentrations derived from literature were used to perform visual predictive checks and to calculate ratios between simulated and observed AUCs in order to evaluate model performance.ResultsSimulated data were comparable to observed over a broad age range (1 day - 15 y postnatal age), for all drugs investigated. The ratios between observed and simulated AUCs were within 2-fold difference both in plasma and in CSF, indicating acceptable model performance. Disposition of meropenem into the brain was slow and CSF concentrations were lower compared to plasma concentrations. In addition, several days were needed to achieve CSF steady-state concentration.ConclusionsOur paediatric brain PBPK model provides a new tool to predict CSF concentrations in children with and without meningitis and can be used as a template model for other drugs acting in the CNS.Disclosure(s)Nothing to disclose

scholarly journals Natural Polysaccharide Carriers in Brain Delivery: Challenge and Perspective

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1183
Author(s):  
Manuela Curcio ◽  
Giuseppe Cirillo ◽  
Jourdin R. C. Rouaen ◽  
Federica Saletta ◽  
Fiore Pasquale Nicoletta ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Stimuli Responsive ◽  
Drug Bioavailability ◽  
Responsive Materials ◽  
Blood Brain ◽  
Wide Range ◽  
Materials Used ◽  
The Brain

Targeted drug delivery systems represent valuable tools to enhance the accumulation of therapeutics in the brain. Here, the presence of the blood brain barrier strongly hinders the passage of foreign substances, often limiting the effectiveness of pharmacological therapies. Among the plethora of materials used for the development of these systems, natural polysaccharides are attracting growing interest because of their biocompatibility, muco-adhesion, and chemical versatility which allow a wide range of carriers with tailored physico-chemical features to be synthetized. This review describes the state of the art in the field of targeted carriers based on natural polysaccharides over the last five years, focusing on the main targeting strategies, namely passive and active transport, stimuli-responsive materials and the administration route. In addition, in the last section, the efficacy of the reviewed carriers in each specific brain diseases is summarized and commented on in terms of enhancement of either blood brain barrier (BBB) permeation ability or drug bioavailability in the brain.

scholarly journals A Novel Method to Stimulate Lymphatic Clearance of Beta-Amyloid from Mouse Brain Using Non-invasive Music-Induced Opening of the Blood-Brain Barrier with EEG Markers

2021 ◽  
Author(s):  
Oxana Semyachkina-Glushkovskaya ◽  
Alexander Khorovodov ◽  
Ivan Fedosov ◽  
Alexey Pavlov ◽  
Alexander Shirokov ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Mouse Brain ◽  
Protein A ◽  
Magnetic Resonance Tomography ◽  
Confocal Imaging ◽  
Brain Barrier ◽  
Fluctuation Analysis ◽  
Non Invasive ◽  
Blood Brain ◽  
The Brain

The lymphatic system of the brain meninges and head plays a crucial role in the clearance of amyloid-β protein (Aβ), a peptide thought to be pathogenic in Alzheimer’s disease (AD), from the brain. The development of methods to modulate lymphatic clearance of Aβ from the brain coild be a revolutionary step in the therapy of AD. The opening of the blood-brain barrier (OBBB) by focused ultrasound is considered as a possible tool for stimulation of clearance of Aβ from the brain of humans and animals. Here, we propose an alternative method of non-invasive music-induced OBBB that is accompanied by the activation of clearance of fluorescent Aβ (Fαβ) from the mouse brain. Using confocal imaging, fluorescence microscopy and magnetic resonance tomography, we clearly demonstrate that OBBB by music stimulates the movement of Fαβ and Omniscan in the cerebrospinal fluid and lymphatic clearance of Fαβ from the brain. We propose the extended detrended fluctuation analysis (EDFA) as a promising method for the identification of OBBB markers in the electroencephalographic (EEG) patterns. These pilot results suggest that music-induced OBBB and the EDFA analysis of EEG can be a non-invasive, low cost, labelling free, clinical perspective and completely new approach for the treatment and monitoring of AD.

scholarly journals Novel Intrinsic Mechanisms of Active Drug Extrusion at the Blood-Brain Barrier: Potential Targets for Enhancing Drug Delivery to the Brain?

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 966
Author(s):  
Wolfgang Löscher ◽  
Birthe Gericke
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Active Drug ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Metabolic Characteristics ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Blood Neutrophils ◽  
The Brain

The blood-brain barrier (BBB) limits the pharmacotherapy of several brain disorders. In addition to the structural and metabolic characteristics of the BBB, the ATP-driven, drug efflux transporter P-glycoprotein (Pgp) is a selective gatekeeper of the BBB; thus, it is a primary hindrance to drug delivery into the brain. Here, we review the complex regulation of Pgp expression and functional activity at the BBB with an emphasis on recent studies from our laboratory. In addition to traditional processes such as transcriptional regulation and posttranscriptional or posttranslational modification of Pgp expression and functionality, novel mechanisms such as intra- and intercellular Pgp trafficking and intracellular Pgp-mediated lysosomal sequestration in BBB endothelial cells with subsequent disposal by blood neutrophils are discussed. These intrinsic mechanisms of active drug extrusion at the BBB are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the treatment of brain diseases and enhance drug delivery to the brain.

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