scholarly journals miR-98 reduces endothelial dysfunction by protecting blood–brain barrier (BBB) and improves neurological outcomes in mouse ischemia/reperfusion stroke model

2019 ◽  
Vol 40 (10) ◽  
pp. 1953-1965 ◽  
Author(s):  
David L Bernstein ◽  
Viviana Zuluaga-Ramirez ◽  
Sachin Gajghate ◽  
Nancy L Reichenbach ◽  
Boris Polyak ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Inflammatory Factors ◽  
Brain Endothelium ◽  
Blood Brain ◽  
The Brain

Most neurological diseases, including stroke, lead to some degree of blood–brain barrier (BBB) dysfunction. A significant portion of BBB injury is caused by inflammation, due to pro-inflammatory factors produced in the brain, and by leukocyte engagement of the brain endothelium. Recently, microRNAs (miRNAs) have appeared as major regulators of inflammation-induced changes to gene expression in the microvascular endothelial cells (BMVEC) that comprise the BBB. However, miRNAs’ role during cerebral ischemia/reperfusion is still underexplored. Endothelial levels of miR-98 were significantly altered following ischemia/reperfusion insults, both in vivo and in vitro, transient middle cerebral artery occlusion (tMCAO), and oxygen–glucose deprivation (OGD), respectively. Overexpression of miR-98 reduced the mouse’s infarct size after tMCAO. Further, miR-98 lessened infiltration of proinflammatory Ly6CHI leukocytes into the brain following stroke and diminished the prevalence of M1 (activated) microglia within the impacted area. miR-98 attenuated BBB permeability, as demonstrated by changes to fluorescently-labeled dextran penetration in vivo and improved transendothelial electrical resistance (TEER) in vitro. Treatment with miR-98 improved significantly the locomotor impairment. Our study provides identification and functional assessment of miRNAs in brain endothelium and lays the groundwork for improving therapeutic approaches for patients suffering from ischemic attacks.

scholarly journals Cerebromicrovascular endothelial cells are resistant to l-glutamate

2008 ◽  
Vol 295 (4) ◽  
pp. R1099-R1108 ◽  
Author(s):  
Ferenc Domoki ◽  
Béla Kis ◽  
Tamás Gáspár ◽  
Ferenc Bari ◽  
David W. Busija
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Primary Cultures ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Cranial Window ◽  
Blood Brain ◽  
Microvascular Cells

Cerebral microvascular endothelial cells (CMVECs) have recently been implicated as targets of excitotoxic injury by l-glutamate (l-glut) or N-methyl-d-aspartate (NMDA) in vitro. However, high levels of l-glut do not compromise the function of the blood-brain barrier in vivo. We sought to determine whether primary cultures of rat and piglet CMVECs or cerebral microvascular pericytes (CMVPCs) are indeed sensitive to l-glut or NMDA. Viability was unaffected by 8-h exposure to 1–10 mM l-glut or NMDA in CMVECs or CMVPCs isolated from both species. Furthermore, neither 1 mM l-glut nor NMDA augmented cell death induced by 12-h oxygen-glucose deprivation in rat CMVECs or by 8-h medium withdrawal in CMVPCs. Additionally, transendothelial electrical resistance of rat CMVEC-astrocyte cocultures or piglet CMVEC cultures were not compromised by up to 24-h exposure to 1 mM l-glut or NMDA. The Ca2+ ionophore calcimycin (5 μM), but not l-glut (1 mM), increased intracellular Ca2+ levels in rat CMVECs and CMVPCs assessed with fluo-4 AM fluorescence and confocal microscopy. CMVEC-dependent pial arteriolar vasodilation to hypercapnia and bradykinin was unaffected by intracarotid infusion of l-glut in anesthetized piglets by closed cranial window/intravital microscopy. We conclude that cerebral microvascular cells are insensitive and resistant to glutamatergic stimuli in accordance with their in vivo role as regulators of potentially neurotoxic amino acids across the blood-brain barrier.

scholarly journals Lysozyme transport to the brain by liposomes

2018 ◽  
Vol 1 (2) ◽  
pp. 146-161 ◽  
Author(s):  
Mirjam M Nordling-David ◽  
Elior Rachamin ◽  
Etty Grad ◽  
Gershon Golomb
Keyword(s):  
Blood Brain Barrier ◽  
White Blood Cells ◽  
Brain Barrier ◽  
Immunofluorescent Staining ◽  
Phagocytic Cells ◽  
Blood Brain ◽  
The Brain ◽  
Positively Charged

Delivery of drugs into the brain is limited due to poor penetrability of many drugs via the blood-brain barrier. Previous studies have shown that the brain is kept under close surveillance by the immune system, implying that circulating phagocytic cells, such as neutrophils and monocytes, are crossing the blood-brain barrier. We hypothesized that charged liposomes could be transported to the brain following their phagocytosis by circulating monocytes. In this work, we investigated the capacity of circulating monocytes to be exploited as a drug delivery system following IV administration of nano-sized, positively fluorescently labeled liposomes containing the protein lysozyme. Negatively charged fluorescently labeled liposomes were used for comparison. By using a modified thin-film hydration technique, the desired properties of the liposomal formulations were achieved including size, polydispersity index, high drug concentration, and stability. In vitro results showed a significant time-dependent uptake of positively charged liposomes by RAW264.7 cells. In vivo results revealed that circulating white blood cells (mainly monocytes) contained high levels of fluorescently labeled liposomes. Screening of brain sections using confocal microscopy uncovered that a substantial amount of fluorescently labeled liposomes, in contrast to the fluorescent markers in solution, was transported into the brain. In addition, anti-CD68 immunofluorescent staining of brain sections demonstrated co-localization of positively charged liposomes and macrophages in different brain sections. Furthermore, significantly higher levels of lysozyme were detected in brain lysates from rats treated with positively charged liposomes compared to rats treated with lysozyme solution. Taken together this confirms our hypothesis that the designed liposomes were transported to the brain following their phagocytosis by circulating monocytes.

Lipid Nanoformulations in the Treatment of Neuropsychiatric Diseases: An Approach to Overcome the Blood Brain Barrier

2020 ◽  
Vol 21 (9) ◽  
pp. 674-684 ◽  
Author(s):  
Saleha Rehman ◽  
Bushra Nabi ◽  
Faheem Hyder Pottoo ◽  
Sanjula Baboota ◽  
Javed Ali
Keyword(s):  
Blood Brain Barrier ◽  
Water Solubility ◽  
Oral Absorption ◽  
Brain Barrier ◽  
Therapeutic Drug ◽  
Blood Brain ◽  
Neuropsychiatric Diseases ◽  
The Brain

Background: Neuropsychiatric diseases primarily characterized by dementia stand third in the global list of diseases causing disability. The poor water solubility, erratic oral absorption, low bioavailability, poor intestinal absorption, and the impeding action of the blood-brain barrier (BBB) are the major factors limiting the therapeutic feasibility of the antipsychotics. Only a small percentage of antipsychotics reaches the therapeutic target site, which warrants administration of high doses, consequently leading to unwanted side-effects. Hence the main struggle for the effective treatment of neuropsychiatric diseases occurs “at the gates” of the brain, which can be mitigated with the use of a nanotechnology-based platform. Methods: The goal of this review is to undertake a comprehensive study about the role of lipid nanoformulations in facilitating the delivery of antipsychotics across BBB along with the available in vitro and in vivo evidence. Results: Lipid nanoformulations have attained great popularity for the delivery of therapeutics into the brain. Their nanosize helps in overcoming the biological barriers, thereby providing easy BBB translocation of the drugs. Besides, they offer numerous advantages like controlled and targeted drug release, minimizing drug efflux, long storage stability, augmented bioavailability, and reduced adverse drug effects to attain an optimal therapeutic drug concentration in the brain. Moreover, employing alternative routes of administration has also shown promising results. Conclusion: Thus, it can be concluded that the lipid nanoformulations bear immense potential in overcoming the challenges associated with the treatment of neuropsychiatric disorders. However, the area warrants further clinical studies to ensure their commercialization, which could revolutionize the treatment of neuropsychiatric diseases in the coming decades.

scholarly journals Overcoming the Blood-Brain Barrier: Functionalised Chitosan Nanocarriers

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1013 ◽  
Author(s):  
Anna E. Caprifico ◽  
Peter J. S. Foot ◽  
Elena Polycarpou ◽  
Gianpiero Calabrese
Keyword(s):  
Blood Brain Barrier ◽  
Chemical Properties ◽  
Brain Barrier ◽  
Hydroxyl Groups ◽  
Blood Brain ◽  
The Brain ◽  
Major Impediment ◽  
And Chemical Properties

The major impediment to the delivery of therapeutics to the brain is the presence of the blood-brain barrier (BBB). The BBB allows for the entrance of essential nutrients while excluding harmful substances, including most therapeutic agents; hence, brain disorders, especially tumours, are very difficult to treat. Chitosan is a well-researched polymer that offers advantageous biological and chemical properties, such as mucoadhesion and the ease of functionalisation. Chitosan-based nanocarriers (CsNCs) establish ionic interactions with the endothelial cells, facilitating the crossing of drugs through the BBB by adsorptive mediated transcytosis. This process is further enhanced by modifications of the structure of chitosan, owing to the presence of reactive amino and hydroxyl groups. Finally, by permanently binding ligands or molecules, such as antibodies or lipids, CsNCs have showed a boosted passage through the BBB, in both in vivo and in vitro studies which will be discussed in this review.

scholarly journals Nanoparticles Based on Quaternary Ammonium Chitosan-methyl-β-cyclodextrin Conjugate for the Neuropeptide Dalargin Delivery to the Central Nervous System: An In Vitro Study

Pharmaceutics ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 5
Author(s):  
Chiara Migone ◽  
Letizia Mattii ◽  
Martina Giannasi ◽  
Stefania Moscato ◽  
Andrea Cesari ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Quaternary Ammonium ◽  
Oral Absorption ◽  
In Vitro Study ◽  
Brain Barrier ◽  
Mucosal Barrier ◽  
Blood Brain ◽  
The Brain

Peptide oral administration is a hard goal to reach, especially if the brain is the target site. The purpose of the present study was to set up a vehicle apt to promote oral absorption of the neuropeptide dalargin (DAL), allowing it to cross the intestinal mucosal barrier, resist enzymatic degradation, and transport drugs to the brain after crossing the blood–brain barrier. Therefore, a chitosan quaternary ammonium derivative was synthesized and conjugated with methyl-β-cyclodextrin to prepare DAL-medicated nanoparticles (DAL-NP). DAL-NP particle size was 227.7 nm, zeta potential +8.60 mV, encapsulation efficiency 89%. DAL-NP protected DAL from degradation by chymotrypsin or pancreatin and tripled DAL degradation time compared to non-encapsulated DAL. Use of DAL-NP was safe for either Caco-2 or bEnd.3 cells, with the latter selected as a blood–brain barrier model. DAL-NP could also cross either the Caco-2 or bEnd.3 monolayer by the transepithelial route. The results suggest a potential DAL-NP ability to transport to the brain a DAL dose fraction administered orally, although in vivo experiments will be needed to confirm the present data obtained in vitro.

Organic Cation Transporters are Involved in Fluoxetine Transport Across the Blood-Brain Barrier in Vivo and in Vitro

2021 ◽  
Vol 18 ◽  
Author(s):  
Min Wang ◽  
Yingying Sun ◽  
Bingying Hu ◽  
Zhisheng He ◽  
Shanshan Chen ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Cellular Uptake ◽  
Organic Cation ◽  
Brain Barrier ◽  
Organic Cation Transporters ◽  
Cellular Accumulation ◽  
Blood Brain ◽  
The Brain

Background : The research and development of drugs for the treatment of central nervous system diseases faces many challenges at present. One of the most important questions to be answered is, how does the drug cross the blood-brain barrier to get to the target site for pharmacological action. Fluoxetine is widely used in clinical antidepressant therapy. However, the mechanism by which fluoxetine passes through the BBB also remains unclear. Under physiological pH conditions, fluoxetine is an organic cation with a relatively small molecular weight (<500), which is in line with the substrate characteristics of organic cation transporters (OCTs). Therefore, this study aimed to investigate the interaction of fluoxetine with OCTs at the BBB and BBB-associated efflux transporters. This is of great significance for fluoxetine to better treat depression. Moreover, it can provide a theoretical basis for clinical drug combinations. Methods: In vitro BBB model was developed using human brain microvascular endothelial cells (hCMEC/D3), and the cellular accumulation was tested in the presence or absence of transporter inhibitors. In addition, an in vivo trial was performed in rats to investigate the effect of OCTs on the distribution of fluoxetine in the brain tissue. Fluoxetine concentration was determined by a validated UPLC-MS/MS method. Results: The results showed that amantadine (an OCT1/2 inhibitor) and prazosin (an OCT1/3 inhibitor) significantly decreased the cellular accumulation of fluoxetine (P <.001). Moreover, we found that N-methylnicotinamide (an OCT2 inhibitor) significantly inhibited the cellular uptake of 100 and 500 ng/mL fluoxetine (P <.01 and P <.05 respectively). In contrast, corticosterone (an OCT3 inhibitor) only significantly inhibited the cellular uptake of 1000 ng/mL fluoxetine (P <.05). The P-glycoprotein (P-gp) inhibitor, verapamil, and the multidrug resistance resistance-associated proteins (MRPs) inhibitor, MK571, significantly decreased the cellular uptake of fluoxetine. However, intracellular accumulation of fluoxetine was not significantly changed when fluoxetine was incubated with the breast cancer resistance protein (BCRP) inhibitor Ko143. Furthermore, in vivo experiments proved that corticosterone and prazosin significantly inhibited the brain-plasma ratio of fluoxetine at 5.5 h and 12 h, respectively. Conclusion: OCTs might play a significant role in the transport of fluoxetine across the BBB. In addition, P-gp, BCRP, and MRPs seemed not to mediate the efflux transport of fluoxetine.

Sign in / Sign up

Export Citation Format

Share Document