scholarly journals Blood-Brain Barrier Permeable 2-Phenylbenzothiazolyl Iridi-um Complexes as Inhibitors and Probes of Aβ Aggregation

2021 ◽  
Author(s):  
Yiran Huang ◽  
Hanah Na ◽  
Liang Sun ◽  
Karna Terpstra ◽  
Kai Gui ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Day Treatment ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Blood Brain ◽  
Aβ Aggregation ◽  
D Values ◽  
Aβ Fibrils

The aggregation of amyloid β (Aβ) peptides is a significant hallmark of Alzheimer’s Disease (AD) and the inhibition and detection of Aβ aggregates are important for the treatment and diagnosis of AD. Herein, a series of benzothiazole-based luminescent Ir(III) complexes <b>HN-1</b> to <b>HN-8</b> were reported, which exhibit appreciable Aβ aggregation inhibition ability <i>in vitro</i> and in living cells. In addition, they are capable of inducing a fluorescence turn-on effect when binding to Aβ fibrils and oligomers. Most importantly, compared to previously reported cationic metal complexes, the neutral Ir complexes reported here show optimal Log D values, which suggest these compounds should have enhanced blood brain barrier (BBB) permeability. Most importantly, <i>in vivo</i> studies show that the neutral Ir complexes <b>HN-2</b>, <b>HN-3</b>, and <b>HN-8</b> successfully penetrate the BBB and stain amyloid plaques in AD mice brains after a 10-day treatment via i.p. injection, which is unprecedented for Ir(III) complexes, and thus can be used as lead compounds for AD therapeutics development.

scholarly journals Blood-Brain Barrier Permeable 2-Phenylbenzothiazolyl Iridi-um Complexes as Inhibitors and Probes of Aβ Aggregation

2021 ◽  
Author(s):  
Yiran Huang ◽  
Hanah Na ◽  
Liang Sun ◽  
Karna Terpstra ◽  
Kai Gui ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Day Treatment ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Blood Brain ◽  
Aβ Aggregation ◽  
D Values ◽  
Aβ Fibrils

The aggregation of amyloid β (Aβ) peptides is a significant hallmark of Alzheimer’s Disease (AD) and the inhibition and detection of Aβ aggregates are important for the treatment and diagnosis of AD. Herein, a series of benzothiazole-based luminescent Ir(III) complexes <b>HN-1</b> to <b>HN-8</b> were reported, which exhibit appreciable Aβ aggregation inhibition ability <i>in vitro</i> and in living cells. In addition, they are capable of inducing a fluorescence turn-on effect when binding to Aβ fibrils and oligomers. Most importantly, compared to previously reported cationic metal complexes, the neutral Ir complexes reported here show optimal Log D values, which suggest these compounds should have enhanced blood brain barrier (BBB) permeability. Most importantly, <i>in vivo</i> studies show that the neutral Ir complexes <b>HN-2</b>, <b>HN-3</b>, and <b>HN-8</b> successfully penetrate the BBB and stain amyloid plaques in AD mice brains after a 10-day treatment via i.p. injection, which is unprecedented for Ir(III) complexes, and thus can be used as lead compounds for AD therapeutics development.

scholarly journals β-Amyloid Protein Induces Mitophagy-Dependent Ferroptosis Through the CD36/PINK/PARKIN Pathway Leading to Blood-Brain Barrier Destruction in Alzheimer's Disease

2021 ◽  
Author(s):  
li Jianhua ◽  
Li mengyu ◽  
Ge Yangyang ◽  
Chen Jiayi ◽  
Ma Jiamin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanism ◽  
Blood Brain Barrier ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability

Abstract Background Blood-brain barrier (BBB) dysfunction may occur in the onset of Alzheimer's disease (AD). While pericytes are a vital part of the neurovascular unit and the BBB, acting as the gatekeeper of the BBB. Amyloid β (Aβ) deposition and neurofibrillary tangles in the brain are the central pathological features of AD. CD36 promotes vascular amyloid deposition and leads to vascular brain damage, neurovascular dysfunction, and cognitive deficits. However, the molecular mechanism in destroying pericytes of the BBB are still unclear. Objectives To investigate the effect of low-dose Aβ1-40 administration on pericyte outcome and BBB injury molecular mechanism. Methods We selected 6-month-old and 9-month-old APP/PS1 mice and wild-type (WT) mice of the same strain, age, and sex as controls. We assessed the BBB by PET/CT. Brain pericytes were extracted and cocultured with endothelial cells (bEnd.3) to generate an in vitro BBB model to observe the effect of Aβ1-40 on the BBB. Furthermore, we explored the intracellular degradation and related molecular mechanisms of Aβ1-40 after being engulfed in cells through CD36. Results BBB permeability and the number of pericytes decreased in APP/PS1 mice. Aβ1-40 increases the permeability of the BBB in an in vivo model and downregulates the expression of CD36, which reversed the Aβ-induced changes in BBB permeability. Aβ1-40 was phagocytized in pericytes with high expression of CD36. We observed that this molecule inhibited pericyte proliferation, caused mitochondrial damage, and increased mitophagy. Finally, we confirmed that Aβ1-40 induced pericyte mitophagy-dependent ferroptosis through the CD36/PINK1/Parkin pathway. Conclusions PDGFRβ (a marker of pericytes), CD36, and amyloid β colocalized in vitro and in vivo and that Aβ1-40 caused BBB destruction by upregulating the expression of CD36 in pericytes. The mechanism by which Aβ1-40 destroys the BBB involves induction of pericyte mitophagy-dependent ferroptosis through the CD36/PINK1/Parkin pathway.

scholarly journals Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2843
Author(s):  
Stefan Saretz ◽  
Gabriele Basset ◽  
Liridona Useini ◽  
Markus Laube ◽  
Jens Pietzsch ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Pharmaceutical Research ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Blood Brain ◽  
Secretase Activity ◽  
Number Of Patients ◽  
Aging Populations ◽  
A Cell

All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer’s disease (AD). One focus in pharmaceutical research to address this issue is on the reduction of the longer amyloid-β (Aβ) fragments in the brain by modulation of γ-secretase, a membrane-bound protease. R-Flurbiprofen (tarenflurbil) was studied in this regard but failed to show significant improvement in AD patients in a phase 3 clinical trial. This was mainly attributed to its low ability to cross the blood–brain barrier (BBB). Here, we present the synthesis and in vitro evaluation of a racemic meta-carborane analogue of flurbiprofen. By introducing the carborane moiety, the hydrophobicity could be shifted into a more favourable range for the penetration of the blood–brain barrier, evident by a logD7.4 value of 2.0. Furthermore, our analogue retained γ-secretase modulator activity in comparison to racemic flurbiprofen in a cell-based assay. These findings demonstrate the potential of carboranes as phenyl mimetics also in AD research.

Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation

2005 ◽  
Vol 289 (5) ◽  
pp. H2012-H2019 ◽  
Author(s):  
Melissa A. Fleegal ◽  
Sharon Hom ◽  
Lindsay K. Borg ◽  
Thomas P. Davis
Keyword(s):  
Blood Brain Barrier ◽  
Paracellular Permeability ◽  
Cell Permeability ◽  
Brain Barrier ◽  
Cerebral Microvessels ◽  
Permeability Changes ◽  
Blood Brain ◽  
Brain Microvessel

The blood-brain barrier (BBB) is a metabolic and physiological barrier important for maintaining brain homeostasis. The aim of this study was to determine the role of PKC activation in BBB paracellular permeability changes induced by hypoxia and posthypoxic reoxygenation using in vitro and in vivo BBB models. In rat brain microvessel endothelial cells (RMECs) exposed to hypoxia (1% O2-99% N2; 24 h), a significant increase in total PKC activity was observed, and this was reduced by posthypoxic reoxygenation (95% room air-5% CO2) for 2 h. The expression of PKC-βII, PKC-γ, PKC-η, PKC-μ, and PKC-λ also increased following hypoxia (1% O2-99% N2; 24 h), and these protein levels remained elevated following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Increases in the expression of PKC-ε and PKC-ζ were also observed following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Moreover, inhibition of PKC with chelerythrine chloride (10 μM) attenuated the hypoxia-induced increases in [14C]sucrose permeability. Similar to what was observed in RMECs, total PKC activity was also stimulated in cerebral microvessels isolated from rats exposed to hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min). In contrast, hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min) significantly increased the expression levels of only PKC-γ and PKC-θ in the in vivo hypoxia model. These data demonstrate that hypoxia-induced BBB paracellular permeability changes occur via a PKC-dependent mechanism, possibly by differentially regulating the protein expression of the 11 PKC isozymes.

Refining In Vitro Neurotoxicity Testing — The Development of Blood–Brain Barrier Models

2003 ◽  
Vol 31 (3) ◽  
pp. 273-276 ◽  
Author(s):  
Hanna Tähti ◽  
Heidi Nevala ◽  
Tarja Toimela
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Three Dimensional ◽  
Brain Barrier ◽  
Culture Methods ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
In Vitro Bbb Model

The purpose of this paper is to review the current state of development of advanced in vitro blood–brain barrier (BBB) models. The BBB is a special capillary bed that separates the blood from the central nervous system (CNS) parenchyma. Astrocytes maintain the integrity of the BBB, and, without astrocytic contacts, isolated brain capillary endothelial cells in culture lose their barrier characteristics. Therefore, when developing in vitro BBB models, it is important to add astrocytic factors into the culture system. Recently, novel filter techniques and co-culture methods have made it possible to develop models which resemble the in vivo functions of the BBB in an effective way. With a BBB model, kinetic factors can be added into the in vitro batteries used for evaluating the neurotoxic potential of chemicals. The in vitro BBB model also represents a useful tool for the in vitro prediction of the BBB permeability of drugs, and offers the possibility to scan a large number of drugs for their potential to enter the CNS. Cultured monolayers of brain endothelial cell lines or selected epithelial cell lines, combined with astrocyte and neuron cultures, form a novel three-dimensional technique for the screening of neurotoxic compounds.

scholarly journals Proof-of-Concept Study of Drug Brain Permeability Between in Vivo Human Brain and an in Vitro iPSCs-Human Blood-Brain Barrier Model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gwenaëlle Le Roux ◽  
Rafika Jarray ◽  
Anne-Cécile Guyot ◽  
Serena Pavoni ◽  
Narciso Costa ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Apparent Permeability ◽  
Clinical Drug Development ◽  
Blood Brain

Abstract The development of effective central nervous system (CNS) drugs has been hampered by the lack of robust strategies to mimic the blood-brain barrier (BBB) and cerebrovascular impairments in vitro. Recent technological advancements in BBB modeling using induced pluripotent stem cells (iPSCs) allowed to overcome some of these obstacles, nonetheless the pertinence for their use in drug permeation study remains to be established. This mandatory information requires a cross comparison of in vitro and in vivo pharmacokinetic data in the same species to avoid failure in late clinical drug development. Here, we measured the BBB permeabilities of 8 clinical positron emission tomography (PET) radioligands with known pharmacokinetic parameters in human brain in vivo with a newly developed in vitro iPSC-based human BBB (iPSC-hBBB) model. Our findings showed a good correlation between in vitro and in vivo drug brain permeability (R2 = 0.83; P = 0.008) which contrasted with the limited correlation between in vitro apparent permeability for a set of 18 CNS/non-CNS compounds using the in vitro iPSCs-hBBB model and drug physicochemical properties. Our data suggest that the iPSC-hBBB model can be integrated in a flow scheme of CNS drug screening and potentially used to study species differences in BBB permeation.

scholarly journals Baicalein as a Potential Inhibitor against BACE1 and AChE: Mechanistic Comprehension through In Vitro and Computational Approaches

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2694 ◽  
Author(s):  
Jin Han ◽  
Yeongseon Ji ◽  
Kumju Youn ◽  
GyuTae Lim ◽  
Jinhyuk Lee ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Efflux Pump ◽  
Critical Role ◽  
Brain Barrier ◽  
Hydroxyl Groups ◽  
Binding Interaction ◽  
In Silico Docking ◽  
Blood Brain

One of the major neurodegenerative features of Alzheimer’s disease (AD) is the presence of neurotoxic amyloid plaques composed of amyloid beta peptide (Aβ). β-Secretase (BACE1) and acetylcholinesterase (AChE), which promote Aβ fibril formation, have become attractive therapeutic targets for AD. P-glycoprotein (P-gp), the major efflux pump of the blood-brain barrier (BBB), plays a critical role in limiting therapeutic molecules. In pursuit of discovering a natural anti-AD candidate, the bioactivity, physicochemical, drug-likeness, and molecular docking properties of baicalein, a major compound from Scutellaria baicalensis, was investigated. Baicalein exhibited strong BACE1 and AChE inhibitory properties (IC50 23.71 ± 1.91 µM and 45.95 ± 3.44 µM, respectively) and reacted in non-competitive and competitive manners with substrates, respectively. in Silico docking analysis was in full agreement with the in vitro results, demonstrating that the compound exhibited powerful binding interaction with target enzymes. Particularly, three continuous hydroxyl groups on the A ring demonstrated strong H-bond binding properties. It is also noteworthy that baicalein complied with all requirements of Lipinski’s rule of five by its optimal physicochemical properties for both oral bioavailability and blood–brain barrier permeability. Overall, the present study strongly demonstrated the possibility of baicalein having in vivo pharmacological efficacy for specific targets in the prevention and/or treatment of AD.

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