Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders

Xiao, Minjia; Zhi, Xu; Yang, Baofeng; Lan, Ziwei; Fang, Fang

doi:10.3389/fnins.2020.00764

Cited by 81 publications

(64 citation statements)

References 223 publications

(280 reference statements)

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“…Biomarkers are considered essential for the monitoring response to therapies that act within the CNS. Many biomarkers, such as cytokines and chemokines, are present in the blood or CSF as a consequence of disease pathology (Kothur et al, 2016), loss of BBB integrity (Xiao et al, 2020), or are indicators of neuronal damage such as increased levels of neurofilament (El Ayoubi and Khoury, 2017), or decreased N-acetyl-aspartate levels on magnetic resonance spectroscopy (MRS) (Narayana, 2005). In MS, the use of different in vivo imaging techniques during the course of the disease have been proposed to monitor therapeutic responses within the CNS.…”

Section: Monitoring Intra-cns Impact Of Dmtsmentioning

confidence: 99%

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis

Correale

Halfón

Jack

et al. 2021

Multiple Sclerosis and Related Disorders

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With the recent approval of cladribine tablets, siponimod and ozanimod, there has been a renewed interest into the extent to which these current generation disease-modifying therapies (DMTs) are able to cross into the central nervous system (CNS), and how this penetration of the blood-brain barrier (BBB) may influence their ability to treat multiple sclerosis (MS).The integrity of the CNS is maintained by the BBB, blood-cerebrospinal fluid barrier, and the arachnoid barrier, which all play an important role in preserving the immunological environment and homeostasis within the CNS. The integrity of the BBB decreases during the course of MS, with a putative temporal relationship to disease worsening. Furthermore, it is currently considered that progression of the disease is mediated mainly by resident cells of the CNS.The existing literature provides evidence to show that some of the current generation DMTs for MS are able to penetrate the CNS and potentially exert direct effects on CNS-resident cells, in particular the CNS-penetrating prodrugs cladribine and fingolimod, and other sphingosine-1 phosphate receptor modulators; siponimod and ozanimod. Other current generation DMTs appear to be restricted to the periphery due to their high molecular weight or physicochemical properties.As more effective brain penetrant therapies are developed for the treatment of MS, there is a need to understand whether the potential for direct effects within the CNS are of significance, and whether this brings additional benefits over and above treatment effects mediated in the periphery. In turn, this will require an improved understanding of the structure and function of the BBB, the role it plays in MS and subsequent treatments.This narrative review summarizes the data supporting the biological plausibility of a potential benefit from therapeutic molecules entering the CNS, and discusses the potential significance in the current and future treatment of MS.

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Section: Monitoring Intra-cns Impact Of Dmtsmentioning

confidence: 99%

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis

Correale

Halfón

Jack

et al. 2021

Multiple Sclerosis and Related Disorders

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“…In addition, the BBB ECs mediate influx transporters to select metabolite uptake from the blood and efflux transporters to remove toxins and waste products from the brain into the blood. In BBB ECs, leukocyte adhesion molecules (LAMs) express very low to suppress immune surveillance in the brain (Quaegebeur et al, 2011 ; Engelhardt and Ransohoff, 2012 ; Chow and Gu, 2015 ; Xiao et al, 2020 ). Thus, the BBB confines the access of neurotoxic compounds, blood cells, and pathogens to the brain (Winkler et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

2021

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The blood–brain barrier (BBB) plays a vital role in maintaining the specialized microenvironment of the neural tissue. It separates the peripheral circulatory system from the brain parenchyma while facilitating communication. Alterations in the distinct physiological properties of the BBB lead to BBB breakdown associated with normal aging and various neurodegenerative diseases. In this review, we first briefly discuss the aging process, then review the phenotypes and mechanisms of BBB breakdown associated with normal aging that further cause neurodegeneration and cognitive impairments. We also summarize dementia such as Alzheimer's disease (AD) and vascular dementia (VaD) and subsequently discuss the phenotypes and mechanisms of BBB disruption in dementia correlated with cognition decline. Overlaps between AD and VaD are also discussed. Techniques that could identify biomarkers associated with BBB breakdown are briefly summarized. Finally, we concluded that BBB breakdown could be used as an emerging biomarker to assist to diagnose cognitive impairment associated with normal aging and dementia.

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“…The BBB works by regulating the exchange of substances from circulation to the brain. A defect or loss of integrity in the BBB can contribute to a variety of CNS diseases (40,41). Epithelial tight junctions are critical features for maintaining the structural integrity of the BBB.…”

Section: Blood Brain Barriermentioning

confidence: 99%

Nutritional Supplementation of Naturally Occurring Vitamin D to Improve Hemorrhagic Stroke Outcomes

et al. 2021

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Vitamin D deficiency, if left untreated, is associated with bone disorders, cardiovascular damage, and an increased risk of ischemic stroke. While there are various nutritional options for the natural intake of vitamin D, we hope to elucidate the potential mechanisms dietary vitamin D may play in hemorrhagic stroke pathology. This scoping review outlines findings from studies relevant to the biochemical activity of vitamin D, the impact of vitamin D deficiency on hemorrhagic stroke outcomes, and the potential benefit of nutritional vitamin D on hemorrhagic stroke outcomes. Here, we analyze the relevant factors that can lead to vitamin D deficiency, and subsequently, a higher risk of hemorrhagic stroke incidence with worsened subsequent outcomes. The neuroprotective mechanisms through which vitamin D works to attenuate hemorrhagic stroke onset and post-stroke outcomes have not yet been thoroughly examined. However, researchers have proposed several potential protective mechanisms, including reduction of blood brain barrier disturbance by inhibiting the production of reactive oxygen species, mitigation of inflammation through a reduction of levels of proinflammatory cytokines, and prevention of cerebral vasospasm and delayed cerebral ischemia following subarachnoid hemorrhage and intracerebral hemorrhage. While more research is needed and there are limitations to vitamin D supplementation, vitamin D as a whole may play a significant role in the dynamics of hemorrhagic stroke. Further research should focus on expanding our understanding of the neuroprotective capacity and mechanisms of vitamin D, as well as how vitamin D supplementation could serve as an effective course of treatment of hemorrhagic strokes.

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Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders

Cited by 81 publications

References 223 publications

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

Nutritional Supplementation of Naturally Occurring Vitamin D to Improve Hemorrhagic Stroke Outcomes

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