Fluorescein Isothiocyanate (FITC)‐Dextran Extravasation as a Measure of Blood‐Brain Barrier Permeability

Natarajan, Reka; Northrop, Nicole A.; Yamamoto, Bryan K.

doi:10.1002/cpns.25

Cited by 73 publications

(50 citation statements)

References 21 publications

(17 reference statements)

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“…-Must be used at low concentrations to avoid in vivo toxicity. (Willis et al, 2010;Saunders et al, 2015;Natarajan et al, 2017;Devraj et al, 2018) Horseradish peroxidase (HRP)…”

Section: Molecular Composition and Regulation Of Tjs At The Bbbmentioning

confidence: 99%

Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders

et al. 2020

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The blood-brain barrier (BBB) allows the brain to selectively import nutrients and energy critical to neuronal function while simultaneously excluding neurotoxic substances from the peripheral circulation. In contrast to the highly permeable vasculature present in most organs that reside outside of the central nervous system (CNS), the BBB exhibits a high transendothelial electrical resistance (TEER) along with a low rate of transcytosis and greatly restricted paracellular permeability. The property of low paracellular permeability is controlled by tight junction (TJ) protein complexes that seal the paracellular route between apposing brain microvascular endothelial cells. Although tight junction protein complexes are principal contributors to physical barrier properties, they are not static in nature. Rather, tight junction protein complexes are highly dynamic structures, where expression and/or localization of individual constituent proteins can be modified in response to pathophysiological stressors. These stressors induce modifications to tight junction protein complexes that involve de novo synthesis of new protein or discrete trafficking mechanisms. Such responsiveness of BBB tight junctions to diseases indicates that these protein complexes are critical for maintenance of CNS homeostasis. In fulfillment of this vital role, BBB tight junctions are also a major obstacle to therapeutic drug delivery to the brain. There is an opportunity to overcome this substantial obstacle and optimize neuropharmacology via acquisition of a detailed understanding of BBB tight junction structure, function, and regulation. In this review, we discuss physiological characteristics of tight junction protein complexes and how these properties regulate delivery of therapeutics to the CNS for treatment of neurological diseases. Specifically, we will discuss modulation of tight junction structure, function, and regulation both in the context of disease states and in the setting of pharmacotherapy. In particular, we will highlight how these properties can be potentially manipulated at the molecular level to increase CNS drug levels via paracellular transport to the brain.

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“…-Must be used at low concentrations to avoid in vivo toxicity. (Willis et al, 2010;Saunders et al, 2015;Natarajan et al, 2017;Devraj et al, 2018) Horseradish peroxidase (HRP)…”

Section: Molecular Composition and Regulation Of Tjs At The Bbbmentioning

confidence: 99%

Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders

et al. 2020

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“…The peri-infarcted zones in the tMCAO mice were observed by TPLSM (FVMPE-RS; Olympus Corp., Tokyo, Japan). To assess BBB integrity [ 44 ], 0.1 mL fluorescein isothiocyanate-labeled dextran (FITC-dextran, 10 kDa, 100 mg·mL −1 ; Sigma-Aldrich Corp., St. Louis, MO, USA) was injected through the tail vein at 4 h after tMCAO to visualize the degree of extravasation of the brain microvessels. Capillaries 50 μ m below the surface of the cerebral cortex of each mouse were randomly selected to observe changes in BBB permeability and morphological destruction of the brain microvessels.…”

Section: Methodsmentioning

confidence: 99%

Network Pharmacology‐Based Approach to Revealing Biological Mechanisms of Qingkailing Injection against IschemicStroke: Focusing on Blood‐Brain Barrier

Zhang

Wang

Cheng

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Ischemic stroke is the most common type of cerebrovascular accident worldwide. It causes long-term disability and death. Qingkailing (QKL) injection is a traditional Chinese patent medicine which has been clinically applied in the treatment of ischemic stroke for nearly thirty years. In the present study, network pharmacology combined with experimentation was used to elucidate the mechanisms of QKL. ADME screening and target prediction identified 62 active compounds and 275 targets for QKL. Topological screening of the protein-protein interaction (PPI) network was used to build a core PPI network consisting of 408 nodes and 17,830 edges. KEGG enrichment indicated that the main signaling pathway implicated in ischemic stroke involved hypoxia-inducible factor-1 (HIF-1). Experimentation showed that QKL alleviated neurological deficits, brain infraction, blood-brain barrier (BBB) leakage, and tight junction degeneration in a mouse ischemic stroke model. Two-photon laser scanning microscopy was used to evaluate BBB permeability and cerebral microvessel structure in living mice. HIF-1α, matrix metalloproteinase-9 (MMP-9), and tight junction proteins such as occludin, zonula occludins-1 (ZO-1), claudin-5, and VE-Cadherin were measured by western blotting. QKL upregulated ZO-1 and downregulated HIF-1α and MMP-9. QKL has a multiapproach, multitarget, and synergistic effect against ischemic stroke.

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“…The large size of interendothelial clefts and transendothelial fenestrations as well as their increased number contribute to the high degree of BBTB permeability. The degree of BBB and BBTB permeability is traditionally measured by using differentsized fluorescently labeled dextrans (54)(55)(56)(57)(58). The customizability of uniformly sized dextrans and their reactivity with fluorescent molecules such as fluorescein isothiocyanate (FITC) create easily assembled probes that can be visualized for interrogating BBB permeability.…”

Section: Degree Of Bbtb Endothelium Permeabilitymentioning

confidence: 99%

Blood-Brain Barrier, Blood-Brain Tumor Barrier, and Fluorescence-Guided Neurosurgical Oncology: Delivering Optical Labels to Brain Tumors

et al. 2020

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Recent advances in maximum safe glioma resection have included the introduction of a host of visualization techniques to complement intraoperative white-light imaging of tumors. However, barriers to the effective use of these techniques within the central nervous system remain. In the healthy brain, the blood-brain barrier ensures the stability of the sensitive internal environment of the brain by protecting the active functions of the central nervous system and preventing the invasion of microorganisms and toxins. Brain tumors, however, often cause degradation and dysfunction of this barrier, resulting in a heterogeneous increase in vascular permeability throughout the tumor mass and outside it. Thus, the characteristics of both the blood-brain and blood-brain tumor barriers hinder the vascular delivery of a variety of therapeutic substances to brain tumors. Recent developments in fluorescent visualization of brain tumors offer improvements in the extent of maximal safe resection, but many of these fluorescent agents must reach the tumor via the vasculature. As a result, these fluorescence-guided resection techniques are often limited by the extent of vascular permeability in tumor regions and by the failure to stain the full volume of tumor tissue. In this review, we describe the structure and function of both the blood-brain and blood-brain tumor barriers in the context of the current state of fluorescence-guided imaging of brain tumors. We discuss features of currently used techniques for fluorescence-guided brain tumor resection, with an emphasis on their interactions with the blood-brain and blood-tumor barriers. Finally, we discuss a selection of novel preclinical techniques that have the potential to enhance the delivery of therapeutics to brain tumors in spite of the barrier properties of the brain.

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Fluorescein Isothiocyanate (FITC)‐Dextran Extravasation as a Measure of Blood‐Brain Barrier Permeability

Cited by 73 publications

References 21 publications

Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders

Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders

Network Pharmacology‐Based Approach to Revealing Biological Mechanisms of Qingkailing Injection against IschemicStroke: Focusing on Blood‐Brain Barrier

Blood-Brain Barrier, Blood-Brain Tumor Barrier, and Fluorescence-Guided Neurosurgical Oncology: Delivering Optical Labels to Brain Tumors

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