scholarly journals TMS-Induced Controlled BBB Opening: Preclinical Characterization and Implications for Treatment of Brain Cancer

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 946
Author(s):  
Udi Vazana ◽  
Lior Schori ◽  
Uri Monsonego ◽  
Evyatar Swissa ◽  
Gabriel S. Pell ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Repetitive Transcranial Magnetic Stimulation ◽  
Unmet Need ◽  
High Amplitude ◽  
Brain Diseases ◽  
Normal Brain ◽  
Safety Level ◽  
The Impact ◽  
The Brain ◽  
Bbb Opening

Proper neuronal function requires strict maintenance of the brain’s extracellular environment. Therefore, passage of molecules between the circulation and brain neuropil is tightly regulated by the blood–brain barrier (BBB). While the BBB is vital for normal brain function, it also restricts the passage of drugs, potentially effective in treating brain diseases, into the brain. Despite previous attempts, there is still an unmet need to develop novel approaches that will allow safe opening of the BBB for drug delivery. We have recently shown in experimental rodents and in a pilot human trial that low-frequency, high-amplitude repetitive transcranial magnetic stimulation (rTMS) allows the delivery of peripherally injected fluorescent and Gd-based tracers into the brain. The goals of this study were to characterize the duration and safety level of rTMS-induced BBB opening and test its capacity to enhance the delivery of the antitumor growth agent, insulin-like growth factor trap, across the BBB. We employed direct vascular and magnetic resonance imaging, as well as electrocorticography recordings, to assess the impact of rTMS on brain vascular permeability and electrical activity, respectively. Our findings indicate that rTMS induces a transient and safe BBB opening with a potential to facilitate drug delivery into the brain.

scholarly journals NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis

BMC Medicine ◽  
2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Shu-zhen Zhang ◽  
Qin-qin Wang ◽  
Qiao-qiao Yang ◽  
Huan-yu Gu ◽  
Yan-qing Yin ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Diphtheria Toxin ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Normal Brain ◽  
Sequencing Analysis ◽  
Brain Functions ◽  
Lps Challenge ◽  
The Impact ◽  
The Brain

Abstract Background Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson’s disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. Methods Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. Results We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. Conclusions These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.

scholarly journals Intranasal Administration as a Route to Deliver Drugs to the Brain (Review)

2021 ◽  
Vol 10 (4) ◽  
pp. 117-127
Author(s):  
N. N. Porfiryeva ◽  
I. I. Semina ◽  
R. I. Moustafine ◽  
V. V. Khutoryanskiy
Keyword(s):  
Phase Transition ◽  
Drug Delivery ◽  
Intranasal Administration ◽  
Proteolytic Enzymes ◽  
Rapid Onset ◽  
The Body ◽  
Brain Diseases ◽  
External Stimulation ◽  
In Situ Gelling ◽  
The Brain

Introduction. Intranasal drug delivery from nose-to-brain is one of the promising approaches for the treatment of brain diseases including neurodegenerative diseases, stroke, brain tumors, etc.Text. Delivery of drugs through the nose has a number of advantages, including the rapid onset of a pharmacological effect, the ability to bypass the blood-brain barrier, avoidance of some side effects and fast and non-invasive route of administration. However, the significant disadvantages of this route are rapid elimination of the drug from the surface of the mucosal membrane, poor penetration of the drug through the nasal mucosa, mucociliary clearance and effects of proteolytic enzymes. Currently, to overcome the above limitations, various approaches are used, including the development of delivery systems from nose-to-brain, which are mucoadhesive, mucus-penetrating and gel-forming systems that facilitate the retention or penetration of drugs through the mucosal membranes. At the same time, high-molecular weight compounds play a significant role in the design of these systems. In particular, mucoadhesive systems can be prepared from cationic and anionic polymers. Recent studies have also shown that interpolyelectrolyte complexes also exhibit mucoadhesive properties. An improvement in mucoadhesive properties of polymers can also be achieved by conjugating various functional groups such as thiols, maleimides, acrylates, methacrylates, catechols, etc. Mucus-penetrating systems can be prepared by PEGylation of nanoparticles, as well as functionalization with some poly(2-oxazolines), polyvinyl alcohol, etc. The mucus-penetrating ability of these polymers has been shown in other mucosal membranes in the body. Finally, increased penetration can be achieved by using mucolytic agents in combination with non-ionic surfactants. Another approach to increase the efficiency of drug delivery from nose-to-brain is the use of in situ gelling systems. Initially, this type of formulation exists as a solution; then a phase transition to gel is observed in response to chemical and physical effects. Depending on the external stimulation of the phase transition, thermo-, pH-, ion-reversible and other systems are known. These systems have shown effectiveness for delivery to the brain by intranasal administration.Conclusion. Effective intranasal delivery of drugs and therapeutic agents to the brain can be achieved by using mucoadhesive, mucus-penetrating, gelling systems and/or their combinations.

scholarly journals Understanding Drug Delivery to the Brain Using Liposome-Based Strategies: Studies that Provide Mechanistic Insights Are Essential

2021 ◽  
Vol 23 (6) ◽  
Author(s):  
Firda Juhairiyah ◽  
Elizabeth C. M. de Lange
Keyword(s):  
Drug Delivery ◽  
Drug Transport ◽  
Animal Studies ◽  
Time Course ◽  
Liposomal Formulation ◽  
Liposomal Drug ◽  
Brain Drug Delivery ◽  
Liposomal Formulations ◽  
The Impact ◽  
The Brain

AbstractBrain drug delivery may be restricted by the blood-brain barrier (BBB), and enhancement by liposome-based drug delivery strategies has been investigated. As access to the human brain is limited, many studies have been performed in experimental animals. Whereas providing interesting data, such studies have room for improvement to provide mechanistic insight into the rate and extent of specifically BBB transport and intrabrain distribution processes that all together govern CNS target delivery of the free drug. This review shortly summarizes BBB transport and current liposome-based strategies to overcome BBB transport restrictions, with the emphasis on how to determine the individual mechanisms that all together determine the time course of free drug brain concentrations, following their administration as such, and in liposomes. Animal studies using microdialysis providing time course information on unbound drug in plasma and brain are highlighted, as these provide the mechanistic information needed to understand BBB drug transport of the drug, and the impact of a liposomal formulations of that drug on BBB transport. Overall, these studies show that brain distribution of a drug administered as liposomal formulation depends on both drug properties and liposomal formulation characteristics. In general, evidence suggests that active transporters at the BBB, either being influx or efflux transporters, are circumvented by liposomes. It is concluded that liposomal formulations may provide interesting changes in BBB transport. More mechanistic studies are needed to understand relevant mechanisms in liposomal drug delivery to the brain, providing an improved basis for its prediction in human using animal data.

scholarly journals Interplay of Good Bacteria and Central Nervous System: Cognitive Aspects and Mechanistic Considerations

2021 ◽  
Vol 15 ◽  
Author(s):  
Mahmoud Salami
Keyword(s):  
Gut Microbiota ◽  
Cognitive Processing ◽  
Clinical Problem ◽  
The Body ◽  
Brain Diseases ◽  
Normal Brain ◽  
Beneficial Effects ◽  
Normal Brain Function ◽  
The Brain ◽  
Common Clinical Problem

The human gastrointestinal tract hosts trillions of microorganisms that is called “gut microbiota.” The gut microbiota is involved in a wide variety of physiological features and functions of the body. Thus, it is not surprising that any damage to the gut microbiota is associated with disorders in different body systems. Probiotics, defined as living microorganisms with health benefits for the host, can support or restore the composition of the gut microbiota. Numerous investigations have proved a relationship between the gut microbiota with normal brain function as well as many brain diseases, in which cognitive dysfunction is a common clinical problem. On the other hand, increasing evidence suggests that the existence of a healthy gut microbiota is crucial for normal cognitive processing. In this regard, interplay of the gut microbiota and cognition has been under focus of recent researches. In the present paper, I review findings of the studies considering beneficial effects of either gut microbiota or probiotic bacteria on the brain cognitive function in the healthy and disease statuses.

scholarly journals Zebrafish: A Promising Real-Time Model System for Nanotechnology-Mediated Neurospecific Drug Delivery

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Suraiya Saleem ◽  
Rajaretinam Rajesh Kannan
Keyword(s):  
Drug Delivery ◽  
Model System ◽  
Research Community ◽  
Therapeutic Interventions ◽  
Brain Diseases ◽  
Zebrafish Model ◽  
Time Model ◽  
High Fecundity ◽  
Novel Technologies ◽  
The Brain

AbstractDelivering drugs to the brain has always remained a challenge for the research community and physicians. The blood–brain barrier (BBB) acts as a major hurdle for delivering drugs to specific parts of the brain and the central nervous system. It is physiologically comprised of complex network of capillaries to protect the brain from any invasive agents or foreign particles. Therefore, there is an absolute need for understanding of the BBB for successful therapeutic interventions. Recent research indicates the strong emergence of zebrafish as a model for assessing the permeability of the BBB, which is highly conserved in its structure and function between the zebrafish and mammals. The zebrafish model system offers a plethora of advantages including easy maintenance, high fecundity and transparency of embryos and larvae. Therefore, it has the potential to be developed as a model for analysing and elucidating the permeability of BBB to novel permeation technologies with neurospecificity. Nanotechnology has now become a focus area within the industrial and research community for delivering drugs to the brain. Nanoparticles are being developed with increased efficiency and accuracy for overcoming the BBB and delivering neurospecific drugs to the brain. The zebrafish stands as an excellent model system to assess nanoparticle biocompatibility and toxicity. Hence, the zebrafish model is indispensable for the discovery or development of novel technologies for neurospecific drug delivery and potential therapies for brain diseases.

scholarly journals Gut and Brain: Investigating Physiological and Pathological Interactions Between Microbiota and Brain to Gain New Therapeutic Avenues for Brain Diseases

2021 ◽  
Vol 15 ◽  
Author(s):  
Gabriele Deidda ◽  
Manuele Biazzo
Keyword(s):  
Gut Microbiota ◽  
Therapeutic Strategy ◽  
Brain Diseases ◽  
Microbial Populations ◽  
Normal Brain ◽  
Neuronal Populations ◽  
Brain Physiology ◽  
Pathological Conditions ◽  
The Brain

Brain physiological functions or pathological dysfunctions do surely depend on the activity of both neuronal and non-neuronal populations. Nevertheless, over the last decades, compelling and fast accumulating evidence showed that the brain is not alone. Indeed, the so-called “gut brain,” composed of the microbial populations living in the gut, forms a symbiotic superorganism weighing as the human brain and strongly communicating with the latter via the gut–brain axis. The gut brain does exert a control on brain (dys)functions and it will eventually become a promising valuable therapeutic target for a number of brain pathologies. In the present review, we will first describe the role of gut microbiota in normal brain physiology from neurodevelopment till adulthood, and thereafter we will discuss evidence from the literature showing how gut microbiota alterations are a signature in a number of brain pathologies ranging from neurodevelopmental to neurodegenerative disorders, and how pre/probiotic supplement interventions aimed to correct the altered dysbiosis in pathological conditions may represent a valuable future therapeutic strategy.

scholarly journals Chitosan-Based Nanocarriers for Nose to Brain Delivery

2019 ◽  
Vol 9 (11) ◽  
pp. 2219 ◽  
Author(s):  
Blessing Atim Aderibigbe ◽  
Tobeka Naki
Keyword(s):  
Drug Delivery ◽  
Nasal Mucosa ◽  
Targeted Drug Delivery ◽  
Drug Uptake ◽  
Brain Diseases ◽  
In Vivo Studies ◽  
Brain Targeting ◽  
Prolonged Contact ◽  
Targeted Drug ◽  
The Brain

In the treatment of brain diseases, most potent drugs that have been developed exhibit poor therapeutic outcomes resulting from the inability of a therapeutic amount of the drug to reach the brain. These drugs do not exhibit targeted drug delivery mechanisms, resulting in a high concentration of the drugs in vital organs leading to drug toxicity. Chitosan (CS) is a natural-based polymer. It has unique properties such as good biodegradability, biocompatibility, mucoadhesive properties, and it has been approved for biomedical applications. It has been used to develop nanocarriers for brain targeting via intranasal administration. Nanocarriers such as nanoparticles, in situ gels, nanoemulsions, and liposomes have been developed. In vitro and in vivo studies revealed that these nanocarriers exhibited enhanced drug uptake to the brain with reduced side effects resulting from the prolonged contact time of the nanocarriers with the nasal mucosa, the surface charge of the nanocarriers, the nano size of the nanocarriers, and their capability to stretch the tight junctions within the nasal mucosa. The aforementioned unique properties make chitosan a potential material for the development of nanocarriers for targeted drug delivery to the brain. This review will focus on chitosan-based carriers for brain targeting.

scholarly journals ROS and Brain Diseases: The Good, the Bad, and the Ugly

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Aurel Popa-Wagner ◽  
Smaranda Mitran ◽  
Senthilkumar Sivanesan ◽  
Edwin Chang ◽  
Ana-Maria Buga
Keyword(s):  
Therapeutic Option ◽  
Adult Brain ◽  
Brain Diseases ◽  
Common Denominator ◽  
Related Factor ◽  
Ros Scavenging ◽  
Neuronal Structure ◽  
Neuropsychiatric Diseases ◽  
The Impact ◽  
The Brain

The brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms. This paper reviews the Janus-faced properties of reactive oxygen species. It will describe the positive aspects of moderately induced ROS but it will also outline recent research findings concerning the impact of oxidative and nitrooxidative stress on neuronal structure and function in neuropsychiatric diseases, including major depression. A common denominator of all neuropsychiatric diseases including schizophrenia and ADHD is an increased inflammatory response of the brain caused either by an exposure to proinflammatory agents during development or an accumulation of degenerated neurons, oxidized proteins, glycated products, or lipid peroxidation in the adult brain. Therefore, modulation of the prooxidant-antioxidant balance provides a therapeutic option which can be used to improve neuroprotection in response to oxidative stress. We also discuss the neuroprotective role of the nuclear factor erythroid 2-related factor (Nrf2) in the aged brain in response to oxidative stressors and nanoparticle-mediated delivery of ROS-scavenging drugs. The antioxidant therapy is a novel therapeutic strategy. However, the available drugs have pleiotropic actions and are not fully characterized in the clinic. Additional clinical trials are needed to assess the risks and benefits of antioxidant therapies for neuropsychiatric disorders.

scholarly journals THER-11. PEPTIDE-MEDIATED PERMEABILIZATION OF THE BLOOD-BRAIN BARRIER IMPROVES DRUG DELIVERY TO BRAIN METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i13-i13
Author(s):  
Synnøve Nymark Aasen ◽  
Heidi Espedal ◽  
Christopher Holte ◽  
Olivier Keunen ◽  
Tine Veronika Karlsen ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Plasma Membranes ◽  
Combined Treatment ◽  
Brain Barrier ◽  
Therapeutic Window ◽  
Dce Mri ◽  
Blood Brain ◽  
The Brain ◽  
Bbb Opening

Abstract BACKGROUND: Melanoma patients have a high risk of developing brain metastases, which is associated with a poor prognosis. The blood-brain barrier (BBB) inhibits sufficient drug delivery into metastatic lesions. We investigated the ability of a synthetic peptide (K16ApoE) to permeabilize the BBB for more effective drug treatment. METHODS: DCE-MRI was performed to study the therapeutic window of BBB opening facilitated by K16ApoE. In vivoand in vitroassays were used to determine K16ApoE toxicity and also to obtain mechanistic insight into its action on the BBB. The therapeutic impact of K16ApoE on melanoma metastases was determined together with dabrafenib, which is otherwise known not to cross an intact BBB. RESULTS: DCE-MRI exhibited an effective K16ApoE-mediated BBB opening for up to 1h. Mechanistic studies displayed a dose-dependent effect of K16ApoE caused by induction of endocytosis. At higher concentrations, the peptide also showed unspecific disturbances on plasma membranes. Combined treatment with K16ApoE and dabrafenib reduced the brain metastatic burden in mice compared to dabrafenib. We also showed by PET/CT that the peptide facilitated the delivery of compounds up to 150 kDa into the brain. CONCLUSIONS: We demonstrate a transient opening of the BBB, caused by K16ApoE, that facilitates improved drug-delivery into the brain. This improves the efficacy of drugs that otherwise do not cross the intact BBB.

scholarly journals Physical Activity vs. Redox Balance in the Brain: Brain Health, Aging and Diseases

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 95
Author(s):  
Paweł Sutkowy ◽  
Alina Woźniak ◽  
Celestyna Mila-Kierzenkowska ◽  
Karolina Szewczyk-Golec ◽  
Roland Wesołowski ◽  
...  
Keyword(s):  
Physical Activity ◽  
Physical Exercise ◽  
Current Knowledge ◽  
Redox Balance ◽  
Brain Diseases ◽  
Antidepressant Effect ◽  
Brain Health ◽  
Health Aging ◽  
The Impact ◽  
The Brain

It has been proven that physical exercise improves cognitive function and memory, has an analgesic and antidepressant effect, and delays the aging of the brain and the development of diseases, including neurodegenerative disorders. There are even attempts to use physical activity in the treatment of mental diseases. The course of most diseases is strictly associated with oxidative stress, which can be prevented or alleviated with regular exercise. It has been proven that physical exercise helps to maintain the oxidant–antioxidant balance. In this review, we present the current knowledge on redox balance in the organism and the consequences of its disruption, while focusing mainly on the brain. Furthermore, we discuss the impact of physical activity on aging and brain diseases, and present current recommendations and directions for further research in this area.

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