Looking at the blood–brain barrier: Molecular anatomy and possible investigation approaches

Cardoso, Fernanda C.; Brites, Dora; Brito, Maria Alexandra

doi:10.1016/j.brainresrev.2010.05.003

Cited by 479 publications

(410 citation statements)

References 338 publications

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“…11,13,14 Similarly, we found that in both mouse and human small intestines, blood capillaries are associated to pericytes stained with desmin and enteric glial cells identified with GFAP marker, together forming the "gut-vascular unit" (GVU) (Fig. 1).…”

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confidence: 57%

Gene expression profile of endothelial cells during perturbation of the gut vascular barrier

et al. 2016

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It has been widely demonstrated that tolerance against gut microbiota is compartmentalized to mucosal sites where microbes mostly reside. How the commensal bacteria are excluded from the entrance into the blood stream via intestinal capillaries that are located beneath the gut epithelium was not clear. We recently described the existence of a new anatomical structure, the 'gut vascular barrier' (GVB), both in murine and human intestines that plays a fundamental role in avoiding indiscriminate trafficking of bacteria from the gut into the blood circulation. The vascular barrier integrity could be altered by Salmonella typhimurium, a pathogen capable of systemic dissemination, through the modulation of the Wnt/b-catenin signaling pathway. Here we have analyzed the differences in gut endothelial gene expression profiles during Salmonella infection and have identified some interesting characteristics of endothelial to mesenchymal transition. These findings add new insights in the gut-liver axis. The intestine is continuously exposed to a huge amount of foreign antigens, mostly food proteins and commensal microorganisms. These harmless antigens induce oral tolerance, which is however different when considering gut bacteria or food antigens. Tolerance to food proteins affects both local and systemic immune responses 1 indeed fed soluble antigens can gain access to the lymphatics to reach the mesenteric lymph nodes (mLN) 2 and the blood stream to reach the liver 3 where oral tolerance is established. By contrast, gut microbes are confined at mucosal sites by the mLNs that function like a firewall avoiding the spreading of intestinal microflora through the thoracic duct into the blood circulation. [4][5][6] Therefore at steady state the systemic immune system is left ignorant to the microbiota. Only during intestinal pathology bacteria can reach the liver that acts as a firewall preventing the bacteria from spreading to other systemic sites. 7 How the microbiota recirculates through the lymphatics has been widely studied, while how intestinal bacteria are excluded from the blood circulation was completely unexplored, even though it is known that intestinal capillaries are located just underneath the epithelial layer whereas the lymphatics are much deeper in the lamina propria.In our recent work, we hypothesized the existence of a barrier at the endothelial level, the 'gut vascular barrier' (GVB), 8 that similarly to the blood brain barrier (BBB) is able to control the type of antigens that can translocate into the blood stream and that is not permissive to bacterial penetration.Drawing a parallelism between the well-known BBB and the newly identified GVB many similarities can be found. Both are able to avoid the indiscriminate movement of molecules, cells and bacteria from blood to the brain parenchyma in the BBB and from the intestinal lumen into the blood circulation in the case of the GVB.

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confidence: 57%

Gene expression profile of endothelial cells during perturbation of the gut vascular barrier

et al. 2016

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“…Here, we used the PAMPA-BBB method described by Di et al, 21 which employs a brain lipid porcine membrane. The in vitro permeabilities (Pe) of commercial drugs through lipid membrane extract together with compound SC001 were determined and are described in Supplementary Table 1 22 we could classify compounds as CNS+ when they present a permeability >4.47 × 10 −6 cm s −1 . Based on these results, we can consider that compound SC001 is able to cross the BBB by passive permeation (Supplementary Table 1 nigra pars compacta (SNpc) of adult rats.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

Morales-García

Susín

Alonso‐Gil

et al. 2012

ACS Chem. Neurosci.

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Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a wellestablished cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC 50 = 3.38 ± 0.08 μM. To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood−brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development.

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“…The impermeability properties of the BCECs are supported by astrocytes, pericytes, and neurons that together form the so-called neurovascular unit. 1 The BBB precludes most molecules from entering the central nervous system (CNS) because of the presence of efflux transporters, 2 and molecules must be preferably small in size and lipophilic to enter the brain. Even molecules with these properties have only limited success in crossing the BBB and entering the brain.…”

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confidence: 99%

Uptake and Transport of Superparamagnetic Iron Oxide Nanoparticles through Human Brain Capillary Endothelial Cells

Thomsen

Linemann

Pondman

et al. 2013

ACS Chem. Neurosci.

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ABSTRACT:The blood−brain barrier (BBB) formed by brain capillary endothelial cells (BCECs) constitutes a firm physical, chemical, and immunological barrier, making the brain accessible to only a few percent of potential drugs intended for treatment inside the central nervous system. With the purpose of overcoming the restraints of the BBB by allowing the transport of drugs, siRNA, or DNA into the brain, a novel approach is to use superparamagnetic iron oxide nanoparticles (SPIONs) as drug carriers. The aim of this study was to investigate the ability of fluorescent SPIONs to pass through human brain microvascular endothelial cells facilitated by an external magnet. The ability of SPIONs to penetrate the barrier was shown to be significantly stronger in the presence of an external magnetic force in an in vitro BBB model. Hence, particles added to the luminal side of the in vitro BBB model were found in astrocytes cocultured at a remote distance on the abluminal side, indicating that particles were transported through the barrier and taken up by astrocytes. Addition of the SPIONs to the culture medium did not negatively affect the viability of the endothelial cells. The magnetic force-mediated dragging of SPIONs through BCECs may denote a novel mechanism for the delivery of drugs to the brain.

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Looking at the blood–brain barrier: Molecular anatomy and possible investigation approaches

Cited by 479 publications

References 338 publications

Gene expression profile of endothelial cells during perturbation of the gut vascular barrier

Gene expression profile of endothelial cells during perturbation of the gut vascular barrier

Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

Uptake and Transport of Superparamagnetic Iron Oxide Nanoparticles through Human Brain Capillary Endothelial Cells

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