CNS Barriers: Identifying Knowledge Gaps and Addressing Pending Questions

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (1 July 2023) | Viewed by 4530

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Center for Genomic Medicine (CGM), King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia
Interests: molecular pathology; neurodegeneration; neurodevelopment; neuroscience; cancer genetics
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Special Issue Information

Dear Colleagues,

Insulation of the nervous system from other body compartments is a standing prerequisite for proper neuronal function that has been conserved throughout evolution.  The interface that separates the nervous system from the circulatory system is known as the blood-brain barrier (BBB) and hemolymph-brain barrier in vertebrates and invertebrates, respectively. While these barriers are functionally conserved, their anatomy varies across taxa.

Invertebrates and primitive vertebrates have their neurophil ensheathed by a glial barrier. Vertebrates, on the other hand, have evolved a more complex structure composed of various cell types that vascularize the brain. Regardless of the level of complexity of such barriers they all serve as gatekeepers that maintain homeostasis, control supply of nutrients and prevent the entry of harmful substances. 

In addition to the BBB, the CNS is guarded by various barriers such as blood-cerebrospinal fluid barrier, meningeal barrier, blood-retinal barrier and barriers engulfing lesion core. The BBB is the most studied of all perhaps due to its direct involvement in regulating passage to the brain parenchyma. Despite the large volume of literature on this topic many questions and knowledge gaps remain to be addressed. Precise knowledge of aspects like:

(a) temporal mapping of barrier genesis and developmental stages;(b) region-specific heterogeneity in barrier properties;(c) barrier capacity to adapt to changes in the CNS environment, is currently lacking.

Moreover, key questions such as:

  1. Do barrier properties change across different life stages or different times of the day as part of normal physiology?
  2. It has been shown that changes in physiological factors like physical or mental activity, and metabolic rate induce alterations in the blood flow, however, do their impact extended to modifying the properties or function of the cellular or molecular components of the barrier?
  3. Pathology is usually linked to compromised barrier integrity and subsequently increased permissiveness or leakage, however, it would be interesting to learn if conditions causing an overly restrictive barrier do exist and what pathological consequences they may lead to?

In this issue, we will curate the latest findings and views with the aim to improve our understanding of the biogenesis and function of CNS barriers. Manuscripts answering open questions, addressing knowledge gaps or summarizing current research related to all types of CNS barriers in vertebrates as well as invertebrates are welcome. 

Dr. Bashayer Al Mubarak
Guest Editor

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Published Papers (2 papers)

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Research

15 pages, 3632 KiB  
Article
Endothelial Specific Deletion of Autotaxin Improves Stroke Outcomes
by Susmita Bhattarai, Utsab Subedi, Shrivats Manikandan, Sudha Sharma, Papori Sharma, Chloe Miller, Md Shenuarin Bhuiyan, Srivatsan Kidambi, Vassilis Aidinis, Hong Sun, Sumitra Miriyala and Manikandan Panchatcharam
Cells 2023, 12(3), 511; https://doi.org/10.3390/cells12030511 - 3 Feb 2023
Cited by 6 | Viewed by 2358
Abstract
Autotaxin (ATX) is an extracellular secretory enzyme (lysophospholipase D) that catalyzes the hydrolysis of lysophosphatidyl choline to lysophosphatidic acid (LPA). The ATX–LPA axis is a well-known pathological mediator of liver fibrosis, metastasis in cancer, pulmonary fibrosis, atherosclerosis, and neurodegenerative diseases. Additionally, it is [...] Read more.
Autotaxin (ATX) is an extracellular secretory enzyme (lysophospholipase D) that catalyzes the hydrolysis of lysophosphatidyl choline to lysophosphatidic acid (LPA). The ATX–LPA axis is a well-known pathological mediator of liver fibrosis, metastasis in cancer, pulmonary fibrosis, atherosclerosis, and neurodegenerative diseases. Additionally, it is believed that LPA may cause vascular permeability. In ischemic stroke, vascular permeability leading to hemorrhagic transformation is a major limitation for therapies and an obstacle to stroke management. Therefore, in this study, we generated an endothelial-specific ATX deletion in mice (ERT2 ATX−/−) to observe stroke outcomes in a mouse stroke model to analyze the role of endothelial ATX. The AR2 probe and Evans Blue staining were used to perform the ATX activity and vascular permeability assays, respectively. Laser speckle imaging was used to observe the cerebral blood flow following stroke. In this study, we observed that stroke outcomes were alleviated with the endothelial deletion of ATX. Permeability and infarct volume were reduced in ERT2 ATX−/− mice compared to ischemia–reperfusion (I/R)-only mice. In addition, the cerebral blood flow was retained in ERT2 ATX−/− compared to I/R mice. The outcomes in the stroke model are alleviated due to the limited LPA concentration, reduced ATX concentration, and ATX activity in ERT2 ATX−/− mice. This study suggests that endothelial-specific ATX leads to increased LPA in the brain vasculature following ischemic–reperfusion and ultimately disrupts vascular permeability, resulting in adverse stroke outcomes. Full article
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13 pages, 1574 KiB  
Article
Computational Approach to Drug Penetration across the Blood-Brain and Blood-Milk Barrier Using Chromatographic Descriptors
by Wanat Karolina, Rojek Agata and Brzezińska Elżbieta
Cells 2023, 12(3), 421; https://doi.org/10.3390/cells12030421 - 27 Jan 2023
Cited by 1 | Viewed by 1455
Abstract
Drug penetration through biological barriers is an important aspect of pharmacokinetics. Although the structure of the blood-brain and blood-milk barriers is different, a connection can be found in the literature between drugs entering the central nervous system (CNS) and breast milk. This study [...] Read more.
Drug penetration through biological barriers is an important aspect of pharmacokinetics. Although the structure of the blood-brain and blood-milk barriers is different, a connection can be found in the literature between drugs entering the central nervous system (CNS) and breast milk. This study was created to reveal such a relationship with the use of statistical modelling. The basic physicochemical properties of 37 active pharmaceutical compounds (APIs) and their chromatographic retention data (TLC and HPLC) were incorporated into calculations as molecular descriptors (MDs). Chromatography was performed in a thin layer format (TLC), where the plates were impregnated with bovine serum albumin to mimic plasma protein binding. Two columns were used in high performance liquid chromatography (HPLC): one with immobilized human serum albumin (HSA), and the other containing an immobilized artificial membrane (IAM). Statistical methods including multiple linear regression (MLR), cluster analysis (CA) and random forest regression (RF) were performed with satisfactory results: the MLR model explains 83% of the independent variable variability related to CNS bioavailability; while the RF model explains up to 87%. In both cases, the parameter related to breast milk penetration was included in the created models. A significant share of reversed-phase TLC retention values was also noticed in the RF model. Full article
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