Publications by authors named "William A Banks"

315 Publications

Leptin and the Blood-Brain Barrier: Curiosities and Controversies.

Authors:
William A Banks

Compr Physiol 2021 09 23;11(4):2351-2369. Epub 2021 Sep 23.

Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.

Leptin for over 25 years has been a central theme in the study of appetite, obesity, and starvation. As the major site of leptin production is peripheral, and the site of action of greatest interest is the hypothalamus, how leptin accesses the central nervous system (CNS) and crosses the blood-brain barrier (BBB) has been of great interest. We review here the ongoing research that addresses fundamental questions such as the sites of leptin resistances in obesity and other conditions, the causes of resistances and their relations to one another, the three barrier sites of entry into the CNS, why recent studies using suprapharmacological doses cannot address these questions but give insight into nonsaturable entry of leptin into the CNS, and how that might be useful in using leptin therapeutically. The current status of the controversy of whether the short form of the leptin receptor acts as the BBB leptin transporter and how obesity may transform leptin transport is reviewed. Review of these and other topics summarizes in a new appreciation of what leptin may have actually evolved to do and what physiological role leptin resistance may play. © 2021 American Physiological Society. Compr Physiol 11:1-19, 2021.
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http://dx.doi.org/10.1002/cphy.c200017DOI Listing
September 2021

Effects of apolipoprotein E isoform, sex, and diet on insulin BBB pharmacokinetics in mice.

Sci Rep 2021 Sep 20;11(1):18636. Epub 2021 Sep 20.

Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, 98195, USA.

Age, apolipoprotein E (apoE) isoform, sex, and diet can independently affect the risk for the development of Alzheimer's disease (AD). Additionally, synergy between some of these risk factors have been observed. However, the relation between the latter three risk factors has not been investigated. Central nervous system (CNS) insulin resistance is commonly involved in each of these risk factors. CNS insulin is primarily derived from the periphery in which insulin must be transported across the blood-brain barrier (BBB). Additionally, insulin can bind the brain endothelial cell to affect intracellular signaling. Therefore, we hypothesized CNS access to insulin could be affected by the combination of apoE isoform, sex, and diet. We analyzed insulin BBB pharmacokinetics in aged apoE targeted replacement (E3 and E4) male and female mice on a low-fat and high-fat diet. There were differences within males and females due to apoE genotype and diet in insulin interactions at the BBB. These sex-, diet-, and apoE isoform-dependent differences could contribute to the cognitive changes observed due to altered CNS insulin signaling.
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http://dx.doi.org/10.1038/s41598-021-98061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452709PMC
September 2021

Editorial: Application for Nanotechnology for the Treatment of Brain Diseases and Disorders.

Front Bioeng Biotechnol 2021 30;9:743160. Epub 2021 Aug 30.

Centre for Motor Neuron Disease, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.

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http://dx.doi.org/10.3389/fbioe.2021.743160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435573PMC
August 2021

Interactions of Lipids, Lipoproteins, and Apolipoproteins with the Blood-Brain Barrier.

Pharm Res 2021 Sep 13;38(9):1469-1475. Epub 2021 Sep 13.

Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

Lipids and lipoproteins are a diverse group of substances and their interactions with the blood-brain barrier (BBB) is similarly diverse. Some lipoproteins such as high density lipoprotein (HDL), apolipoprotein (apo) A-I, apoJ, some free fatty acids, and triglycerides cross the BBB whereas others such as apoE do not. Some forms of cholesterol can cross the BBB and others do not. Lipids can have effects on BBB preservation and function: HDL may protect the BBB during multiple sclerosis, cholesterol can disrupt the BBB, and triglycerides inhibit the transport of leptin across the BBB and the activation of the hypothalamic leptin receptor. ApoE is associated with many effects on the BBB, with the specific isoform apoE4 having detrimental effects. In summary, the diverse ways in which lipids, lipoproteins, and apolipoproteins interact with the BBB is important in both health and disease.
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http://dx.doi.org/10.1007/s11095-021-03098-6DOI Listing
September 2021

Decoding perineuronal net glycan sulfation patterns in the Alzheimer's disease brain.

Alzheimers Dement 2021 Sep 5. Epub 2021 Sep 5.

University of Washington Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA.

The extracellular matrix (ECM) of the brain comprises unique glycan "sulfation codes" that influence neurological function. Perineuronal nets (PNNs) are chondroitin sulfate-glycosaminoglycan (CS-GAG) containing matrices that enmesh neural networks involved in memory and cognition, and loss of PNN matrices is reported in patients with neurocognitive and neuropsychiatric disorders including Alzheimer's disease (AD). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), we show that patients with a clinical diagnosis of AD-related dementia undergo a re-coding of their PNN-associated CS-GAGs that correlates to Braak stage progression, hyperphosphorylated tau (p-tau) accumulation, and cognitive impairment. As these CS-GAG sulfation changes are detectable prior to the regional onset of classical AD pathology, they may contribute to the initiation and/or progression of the underlying degenerative processes and implicate the brain matrix sulfation code as a key player in the development of AD clinicopathology.
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http://dx.doi.org/10.1002/alz.12451DOI Listing
September 2021

Adropin correlates with aging-related neuropathology in humans and improves cognitive function in aging mice.

NPJ Aging Mech Dis 2021 Aug 30;7(1):23. Epub 2021 Aug 30.

Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA.

The neural functions of adropin, a secreted peptide highly expressed in the brain, have not been investigated. In humans, adropin is highly expressed in astrocytes and peaks during critical postnatal periods of brain development. Gene enrichment analysis of transcripts correlating with adropin expression suggests processes relevant to aging-related neurodegenerative diseases that vary with age and dementia state, possibly indicating survivor bias. In people aged <40 y and 'old-old' (>75 y) diagnosed with dementia, adropin correlates positively with genes involved in mitochondrial processes. In the 'old-old' without dementia adropin expression correlates positively with morphogenesis and synapse function. Potent neurotrophic responses in primary cultured neurons are consistent with adropin supporting the development and function of neural networks. Adropin expression in the 'old-old' also correlates positively with protein markers of tau-related neuropathologies and inflammation, particularly in those without dementia. How variation in brain adropin expression affects neurological aging was investigated using old (18-month) C57BL/6J mice. In mice adropin is expressed in neurons, oligodendrocyte progenitor cells, oligodendrocytes, and microglia and shows correlative relationships with groups of genes involved in neurodegeneration and cellular metabolism. Increasing adropin expression using transgenesis improved spatial learning and memory, novel object recognition, resilience to exposure to new environments, and reduced mRNA markers of inflammation in old mice. Treatment with synthetic adropin peptide also reversed age-related declines in cognitive functions and affected expression of genes involved in morphogenesis and cellular metabolism. Collectively, these results establish a link between adropin expression and neural energy metabolism and indicate a potential therapy against neurological aging.
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http://dx.doi.org/10.1038/s41514-021-00076-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405681PMC
August 2021

Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood-Brain Barrier Transport.

Med Sci (Basel) 2021 08 25;9(3). Epub 2021 Aug 25.

Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA.

Rapamycin is an exogenous compound that has been shown to improve cognition in Alzheimer's disease mouse models and can regulate pathways downstream of the insulin receptor signaling pathway. Insulin is also known to improve cognition in rodent models of Alzheimer's disease. Central nervous system (CNS) insulin must first cross the blood-brain barrier (BBB), a specialized network of brain endothelial cells. This transport process is regulated by physiological factors, such as insulin itself, triglycerides, cytokines, and starvation. Since rapamycin treatment can alter the metabolic state of rodents, increase the circulating triglycerides, and acts as a starvation mimetic, we hypothesized rapamycin could alter the rate of insulin transport across the BBB, providing a potential mechanism for the beneficial effects of rapamycin on cognition. Using young male and female CD-1 mice, we measured the effects of rapamycin on the basal levels of serum factors, insulin receptor signaling, vascular binding, and BBB pharmacokinetics. We found chronic rapamycin treatment was able to affect basal levels of circulating serum factors and endothelial cell insulin receptor signaling. In addition, while acute rapamycin treatment did affect insulin binding at the BBB, overall transport was unaltered. Chronic rapamycin slowed insulin BBB transport non-significantly ( = 0.055). These results suggest that rapamycin may not directly impact the transport of insulin at the BBB but could be acting to alter insulin signaling within brain endothelial cells, which can affect downstream signaling.
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http://dx.doi.org/10.3390/medsci9030056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395935PMC
August 2021

Healthy aging and the blood-brain barrier.

Nat Aging 2021 Mar 15;1(3):243-254. Epub 2021 Mar 15.

Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.

The blood-brain barrier (BBB) protects the central nervous system (CNS) from unregulated exposure to the blood and its contents. The BBB also controls the blood-to-brain and brain-to-blood permeation of many substances, resulting in nourishment of the CNS, its homeostatic regulation and communication between the CNS and peripheral tissues. The cells forming the BBB communicate with cells of the brain and in the periphery. This highly regulated interface changes with healthy aging. Here, we review those changes, starting with morphology and disruption. Transporter changes include those for amyloid beta peptide, glucose and drugs. Brain fluid dynamics, pericyte health and basement membrane and glycocalyx compositions are all altered with healthy aging. Carrying the allele leads to an acceleration of most of the BBB's age-related changes. We discuss how alterations in the BBB that occur with healthy aging reflect adaptation to the postreproductive phase of life and may affect vulnerability to age-associated diseases.
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http://dx.doi.org/10.1038/s43587-021-00043-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340949PMC
March 2021

Pitavastatin Ameliorates Lipopolysaccharide-Induced Blood-Brain Barrier Dysfunction.

Biomedicines 2021 Jul 18;9(7). Epub 2021 Jul 18.

Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98108, USA.

Statins have neuroprotective effects on neurological diseases, including a pleiotropic effect possibly related to blood-brain barrier (BBB) function. In this study, we investigated the effects of pitavastatin (PTV) on lipopolysaccharide (LPS)-induced BBB dysfunction in an in vitro BBB model comprising cocultured primary mouse brain endothelial cells, pericytes, and astrocytes. LPS (1 ng/mL, 24 h) increased the permeability and lowered the transendothelial electrical resistance of the BBB, and the co-administration of PTV prevented these effects. LPS increased the release of interleukin-6, granulocyte colony-stimulating factor, keratinocyte-derived chemokine, monocyte chemotactic protein-1, and regulated on activation, normal T-cell expressed and secreted from the BBB model. PTV inhibited the LPS-induced release of these cytokines. These results suggest that PTV can ameliorate LPS-induced BBB dysfunction, and these effects might be mediated through the inhibition of LPS-induced cytokine production. Clinically, therapeutic approaches using statins combined with novel strategies need to be designed. Our present finding sheds light on the pharmacological significance of statins in the treatment of central nervous system diseases.
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http://dx.doi.org/10.3390/biomedicines9070837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301395PMC
July 2021

Characterization of systemic immunosuppression by IDH mutant glioma small extracellular vesicles.

Neuro Oncol 2021 Jul 13. Epub 2021 Jul 13.

UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Background: Gliomas are the most common primary brain tumors and are universally fatal. Mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) define a distinct glioma subtype associated with an immunosuppressive tumor microenvironment. Mechanisms underlying systemic immunosuppression in IDH mutant (mutIDH) gliomas are largely unknown. Here, we define genotype-specific local and systemic tumor immunomodulatory functions of tumor-derived glioma exosomes (TEX).

Methods: TEX produced by human and murine wildtype and mutant IDH glioma cells (wtIDH and mutIDH, respectively) were isolated by size exclusion chromatography (SEC). TEX morphology, size, quantity, molecular profiles and biodistribution were characterized. TEX were injected into naive and tumor-bearing mice, and the local and systemic immune microenvironment composition was characterized.

Results: Using in vitro and in vivo glioma models, we show that mutIDH TEX are more numerous, possess distinct morphological features and are more immunosuppressive than wtIDH TEX. mutIDH TEX cargo mimics their parental cells, and induces systemic immune suppression in naive and tumor-bearing mice. TEX derived from mutIDH gliomas and injected into wtIDH tumor-bearing mice reduce tumor-infiltrating effector lymphocytes, dendritic cells and macrophages, and increase circulating monocytes. Astonishingly, mutIDH TEX injected into brain tumor-bearing syngeneic mice accelerate tumor growth and increase mortality compared with wtIDH TEX.

Conclusions: Targeting of mutIDH TEX represents a novel therapeutic approach in gliomas.
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http://dx.doi.org/10.1093/neuonc/noab153DOI Listing
July 2021

Corrigendum to "Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity" [Journal of Controlled Release 191 (2014) 34-46].

J Control Release 2021 Jul 7. Epub 2021 Jul 7.

Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Faculty of Chemistry, M.V. Lomonosov Moscow State University, 119,899 Moscow, Russia. Electronic address:

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http://dx.doi.org/10.1016/j.jconrel.2021.07.001DOI Listing
July 2021

Development of Novel Therapeutics Targeting the Blood-Brain Barrier: From Barrier to Carrier.

Adv Sci (Weinh) 2021 08 3;8(16):e2101090. Epub 2021 Jun 3.

School of Pharmacy, Henan University, Kaifeng, 475001, China.

The blood-brain barrier (BBB) is a highly specialized neurovascular unit, initially described as an intact barrier to prevent toxins, pathogens, and potentially harmful substances from entering the brain. An intact BBB is also critical for the maintenance of normal neuronal function. In cerebral vascular diseases and neurological disorders, the BBB can be disrupted, contributing to disease progression. While restoration of BBB integrity serves as a robust biomarker of better clinical outcomes, the restrictive nature of the intact BBB presents a major hurdle for delivery of therapeutics into the brain. Recent studies show that the BBB is actively engaged in crosstalk between neuronal and the circulatory systems, which defines another important role of the BBB: as an interfacing conduit that mediates communication between two sides of the BBB. This role has been subject to extensive investigation for brain-targeted drug delivery and shows promising results. The dual roles of the BBB make it a unique target for drug development. Here, recent developments and novel strategies to target the BBB for therapeutic purposes are reviewed, from both barrier and carrier perspectives.
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http://dx.doi.org/10.1002/advs.202101090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373165PMC
August 2021

Deficient Leptin Cellular Signaling Plays a Key Role in Brain Ultrastructural Remodeling in Obesity and Type 2 Diabetes Mellitus.

Int J Mol Sci 2021 May 21;22(11). Epub 2021 May 21.

Geriatrics Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, 1660 S. Columbian Way, 810C/Bldg 1, Seattle, WA 98108, USA.

The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer's disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and models) or the novel leptin deficiency (BTBR model).
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http://dx.doi.org/10.3390/ijms22115427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196569PMC
May 2021

Interactions of SARS-CoV-2 with the Blood-Brain Barrier.

Int J Mol Sci 2021 Mar 6;22(5). Epub 2021 Mar 6.

Geriatric Research Education and Clinical Center, VA Puget Sound Healthcare System, Seattle, WA 98108, USA.

Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood-brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.
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http://dx.doi.org/10.3390/ijms22052681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961671PMC
March 2021

Traumatic Brain Injury Broadly Affects GABAergic Signaling in Dentate Gyrus Granule Cells.

eNeuro 2021 May-Jun;8(3). Epub 2021 May 5.

Epilepsy Center of Excellence, VA Puget Sound Health Care System, Seattle, WA 98108

Traumatic brain injury (TBI) causes cellular and molecular alterations that contribute to neuropsychiatric disease and epilepsy. GABAergic dysfunction figures prominently in the pathophysiology of TBI, yet the effects of TBI on tonic inhibition in hippocampus remain uncertain. We used a mouse model of severe TBI [controlled cortical impact (CCI)] to investigate GABAergic signaling in dentate gyrus granule cells (DGGCs). Basal tonic GABA currents were not affected by CCI. However, tonic currents induced by the δ subunit-selective GABA receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 10 μm) were reduced by 44% in DGGCs ipsilateral to CCI (CCI-ipsi), but not in contralateral DGGCs. Reduced THIP currents were apparent one week after injury and persisted up to 15 weeks. The frequency of spontaneous IPSCs (sIPSCs) was reduced in CCI-ipsi cells, but the amplitude and kinetics of sIPSCs were unaffected. Immunohistochemical analysis showed reduced expression of GABA receptor δ subunits and GABA receptor B2 subunits after CCI, by 43% and 40%, respectively. Activation of postsynaptic GABA receptors caused a twofold increase in tonic currents, and this effect was markedly attenuated in CCI-ipsi cells (92% reduction). GABA receptor-activated K currents in DGGCs were also significantly reduced in CCI-ipsi cells, confirming a functional deficit of GABA receptors after CCI. Results indicate broad disruption of GABAergic signaling in DGGCs after CCI, with deficits in both phasic and tonic inhibition and GABA receptor function. These changes are predicted to disrupt operation of hippocampal networks and contribute to sequelae of severe TBI, including epilepsy.
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http://dx.doi.org/10.1523/ENEURO.0055-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116114PMC
July 2021

A historical perspective on the interactions of insulin at the blood-brain barrier.

J Neuroendocrinol 2021 04 12;33(4):e12929. Epub 2021 Jan 12.

Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.

Subsequent to the discovery of insulin in 1921, the role of insulin in the brain has been investigated throughly. The ability of insulin to act within the brain to regulate peripheral glucose levels helped evolve the research surrounding the ability of insulin to be transported into the brain. Investigations aiming to determine the transport of insulin into the brain from the circulation soon followed. Once it was established that insulin could enter the brain, the ability of insulin to bind brain microvessels and regulators of this process were determined. As technology advanced, quantitative measurements to specify the transport rate of insulin across the blood-brain barrier (BBB) and the impact of physiological conditions and diseases were the logical next steps. Lastly, with the advent of genetic mouse models and high-specificity antagonists, the specific role of the insulin receptor in mediating insulin transport could begin to be explored. In this review, we summarise the main findings throughout the decades regarding the interactions of insulin at the BBB.
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http://dx.doi.org/10.1111/jne.12929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052275PMC
April 2021

The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice.

Nat Neurosci 2021 03 16;24(3):368-378. Epub 2020 Dec 16.

Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.

It is unclear whether severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019, can enter the brain. Severe acute respiratory syndrome coronavirus 2 binds to cells via the S1 subunit of its spike protein. We show that intravenously injected radioiodinated S1 (I-S1) readily crossed the blood-brain barrier in male mice, was taken up by brain regions and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney and liver. Intranasally administered I-S1 also entered the brain, although at levels roughly ten times lower than after intravenous administration. APOE genotype and sex did not affect whole-brain I-S1 uptake but had variable effects on uptake by the olfactory bulb, liver, spleen and kidney. I-S1 uptake in the hippocampus and olfactory bulb was reduced by lipopolysaccharide-induced inflammation. Mechanistic studies indicated that I-S1 crosses the blood-brain barrier by adsorptive transcytosis and that murine angiotensin-converting enzyme 2 is involved in brain and lung uptake, but not in kidney, liver or spleen uptake.
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http://dx.doi.org/10.1038/s41593-020-00771-8DOI Listing
March 2021

The neurovascular extracellular matrix in health and disease.

Exp Biol Med (Maywood) 2021 04 10;246(7):835-844. Epub 2020 Dec 10.

Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.

The blood-brain barrier (BBB) is a vital interface that supports normal brain functions. Endothelial cells (ECs) are the main component of the BBB and are highly specialized to govern the transfer of substances into brain. The EC lumen is enmeshed with an extracellular matrix (ECM), known as the endothelial glycocalyx layer (EGL). The lumen-facing EGL is primarily comprised of proteoglycans (PGs) and glycosaminoglycans (GAGs), which function as the first line of defense for blood-to-brain transfer of substances. Circulating factors must first penetrate the EGL before interacting with the EC. The abundance and composition of the PG and GAGs can dictate EGL function, and determine which circulating substances communicate with the ECs. The EGL can interact with circulating factors through physio-chemical interactions with the EC. Some disease states reveal a "thinning" of the EGL that may increase EC interactions with components of the systemic circulation and alter BBB function. EGL changes may also contribute to the cognitive complications of systemic diseases, such as sepsis and diabetes. For decades, researchers have measured how genetic and environmental factors influence the peripheral EGL constituents; however, much less is known about the neurovascular EGL. In this mini-review, we introduce components of the EGL and innovative ways to measure their abundance and composition that may contribute to BBB dysfunction.
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http://dx.doi.org/10.1177/1535370220977195DOI Listing
April 2021

Intranasal Delivery: Effects on the Neuroimmune Axes and Treatment of Neuroinflammation.

Pharmaceutics 2020 Nov 20;12(11). Epub 2020 Nov 20.

Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.

This review highlights the pre-clinical and clinical work performed to use intranasal delivery of various compounds from growth factors to stem cells to reduce neuroimmune interactions. We introduce the concept of intranasal (IN) delivery and the variations of this delivery method based on the model used (i.e., rodents, non-human primates, and humans). We summarize the literature available on IN delivery of growth factors, vitamins and metabolites, cytokines, immunosuppressants, exosomes, and lastly stem cells. We focus on the improvement of neuroimmune interactions, such as the activation of resident central nervous system (CNS) immune cells, expression or release of cytokines, and detrimental effects of signaling processes. We highlight common diseases that are linked to dysregulations in neuroimmune interactions, such as Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, and traumatic brain injury.
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http://dx.doi.org/10.3390/pharmaceutics12111120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699866PMC
November 2020

The microvascular extracellular matrix in brains with Alzheimer's disease neuropathologic change (ADNC) and cerebral amyloid angiopathy (CAA).

Fluids Barriers CNS 2020 Sep 29;17(1):60. Epub 2020 Sep 29.

Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.

Background: The microvasculature (MV) of brains with Alzheimer's disease neuropathologic change (ADNC) and cerebral amyloid angiopathy (CAA), in the absence of concurrent pathologies (e.g., infarctions, Lewy bodies), is incompletely understood.

Objective: To analyze microvascular density, diameter and extracellular matrix (ECM) content in association with ADNC and CAA.

Methods: We examined samples of cerebral cortex and isolated brain microvasculature (MV) from subjects with the National Institute on Aging-Alzheimer's Association (NIA-AA) designations of not-, intermediate-, or high ADNC and from subjects with no CAA and moderate-severe CAA. Cases for all groups were selected with no major (territorial) strokes, ≤ 1 microinfarct in screening sections, and no Lewy body pathology. MV density and diameter were measured from cortical brain sections. Levels of basement membrane (BM) ECM components, the protein product of TNF-stimulated gene-6 (TSG-6), and the ubiquitous glycosaminoglycan hyaluronan (HA) were assayed by western blots or HA ELISA of MV lysates.

Results: We found no significant changes in MV density or diameter among any of the groups. Levels of BM laminin and collagen IV (col IV) were lower in MV isolated from the high ADNC vs. not-ADNC groups. In contrast, BM laminin was significantly higher in MV from the moderate-severe CAA vs. the no CAA groups. TSG-6 and HA content were higher in the presence of both high ADNC and CAA, whereas levels of BM fibronectin and perlecan were similar among all groups.

Conclusions: Cortical MV density and diameter are not appreciably altered by ADNC or CAA. TSG-6 and HA are increased in both ADNC and CAA, with laminin and col IV decreased in the BM of high ADNC, but laminin increased in moderate-severe CAA. These results show that changes in the ECM occur in AD and CAA, but independently of one another, and likely reflect on the regional functioning of the brain microvasculature.
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http://dx.doi.org/10.1186/s12987-020-00219-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525948PMC
September 2020

Hypothalamic perineuronal net assembly is required for sustained diabetes remission induced by fibroblast growth factor 1 in rats.

Nat Metab 2020 10 7;2(10):1025-1033. Epub 2020 Sep 7.

University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.

We recently showed that perineuronal nets (PNNs) enmesh glucoregulatory neurons in the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH), but whether these PNNs play a role in either the pathogenesis of type 2 diabetes (T2D) or its treatment remains unclear. Here we show that PNN abundance within the Arc is markedly reduced in the Zucker diabetic fatty (ZDF) rat model of T2D, compared with normoglycaemic rats, correlating with altered PNN-associated sulfation patterns of chondroitin sulfate glycosaminoglycans in the MBH. Each of these PNN-associated changes is reversed following a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) at a dose that induces sustained diabetes remission in male ZDF rats. Combined with previous work localizing this FGF1 effect to the Arc area, our finding that enzymatic digestion of Arc PNNs markedly shortens the duration of diabetes remission following icv FGF1 injection in these animals identifies these extracellular matrix structures as previously unrecognized participants in the mechanism underlying diabetes remission induced by the central action of FGF1.
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http://dx.doi.org/10.1038/s42255-020-00275-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572652PMC
October 2020

Chronic elevation of plasma vascular endothelial growth factor-A (VEGF-A) is associated with a history of blast exposure.

J Neurol Sci 2020 Oct 18;417:117049. Epub 2020 Jul 18.

Veterans Affairs (VA) Northwest Mental Illness, Research, Education, and Clinical Center (MIRECC), Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. Electronic address:

Mounting evidence points to the significance of neurovascular-related dysfunction in veterans with blast-related mTBI, which is also associated with reduced [F]-fluorodeoxyglucose (FDG) uptake. The goal of this study was to determine whether plasma VEGF-A is altered in veterans with blast-related mTBI and address whether VEGF-A levels correlate with FDG uptake in the cerebellum, a brain region that is vulnerable to blast-related injury 72 veterans with blast-related mTBI (mTBI) and 24 deployed control (DC) veterans with no lifetime history of TBI were studied. Plasma VEGF-A was significantly elevated in mTBIs compared to DCs. Plasma VEGF-A levels in mTBIs were significantly negatively correlated with FDG uptake in cerebellum. In addition, performance on a Stroop color/word interference task was inversely correlated with plasma VEGF-A levels in blast mTBI veterans. Finally, we observed aberrant perivascular VEGF-A immunoreactivity in postmortem cerebellar tissue and not cortical or hippocampal tissues from blast mTBI veterans. These findings add to the limited number of plasma proteins that are chronically elevated in veterans with a history of blast exposure associated with mTBI. It is likely the elevated VEGF-A levels are from peripheral sources. Nonetheless, increasing plasma VEGF-A concentrations correlated with chronically decreased cerebellar glucose metabolism and poorer performance on tasks involving cognitive inhibition and set shifting. These results strengthen an emerging view that cognitive complaints and functional brain deficits caused by blast exposure are associated with chronic blood-brain barrier injury and prolonged recovery in affected regions.
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http://dx.doi.org/10.1016/j.jns.2020.117049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492467PMC
October 2020

Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics.

Biochem Pharmacol 2020 10 2;180:114187. Epub 2020 Aug 2.

Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, Seattle, WA 98108, USA; University of Washington School of Medicine, Division of Gerontology and Geriatric Medicine, Department of Medicine, Seattle, WA 98498, USA. Electronic address:

Among the more promising treatments proposed for Alzheimer's disease (AD) and Parkinson's disease (PD) are those reducing brain insulin resistance. The antidiabetics in the class of incretin receptor agonists (IRAs) reduce symptoms and brain pathology in animal models of AD and PD, as well as glucose utilization in AD cases and clinical symptoms in PD cases after their systemic administration. At least 9 different IRAs are showing promise as AD and PD therapeutics, but we still lack quantitative data on their relative ability to cross the blood-brain barrier (BBB) reaching the brain parenchyma. We consequently compared brain uptake pharmacokinetics of intravenous I-labeled IRAs in adult CD-1 mice over the course of 60 min. We tested single IRAs (exendin-4, liraglutide, lixisenatide, and semaglutide), which bind receptors for one incretin (glucagon-like peptide-1 [GLP-1]), and dual IRAs, which bind receptors for two incretins (GLP-1 and glucose-dependent insulinotropic polypeptide [GIP]), including unbranched, acylated, PEGylated, or C-terminally modified forms (Finan/Ma Peptides 17, 18, and 20 and Hölscher peptides DA3-CH and DA-JC4). The non-acylated and non-PEGylated IRAs (exendin-4, lixisenatide, Peptide 17, DA3-CH and DA-JC4) had significant rates of blood-to-brain influx (Ki), but the acylated IRAs (liraglutide, semaglutide, and Peptide 18) did not measurably cross the BBB. The brain influx of the non-acylated, non-PEGylated IRAs were not saturable up to 1 μg of these drugs and was most likely mediated by adsorptive transcytosis across brain endothelial cells, as observed for exendin-4. Of the non-acylated, non-PEGylated IRAs tested, exendin-4 and DA-JC4 were best able to cross the BBB based on their rate of brain influx, percentage reaching the brain that accumulated in brain parenchyma, and percentage of the systemic dose taken up per gram of brain tissue. Exendin-4 and DA-JC4 thus merit special attention as IRAs well-suited to enter the central nervous system (CNS), thus reaching areas pathologic in AD and PD.
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http://dx.doi.org/10.1016/j.bcp.2020.114187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606641PMC
October 2020

The impact of acute rosiglitazone on insulin pharmacokinetics at the blood-brain barrier.

Endocrinol Diabetes Metab 2020 Jul 4;3(3):e00149. Epub 2020 Jun 4.

Department of Medicine University of Washington Seattle WA USA.

Introduction: CNS insulin levels are decreased and insulin receptor signalling is dampened in Alzheimer's disease (AD). Increasing CNS insulin levels through a variety of methods has been shown to improve memory. Indeed, medications routinely used to improve insulin resistance in type 2 diabetes are now being repurposed for memory enhancement. CNS insulin is primarily derived from the circulation, by an active transport system at the blood-brain barrier (BBB). The goal of this study was to determine whether rosiglitazone (RSG), a drug used to improve insulin sensitivity in type 2 diabetes, could enhance insulin transport at the BBB, as a potential therapeutic for improving memory.

Methods: Using radioactively labelled insulin and the multiple-time regression analysis technique, we measured the rate of insulin BBB transport and level of vascular binding in mice pretreated with vehicle or 10 µg RSG in the presence or absence of an insulin receptor inhibitor.

Results: Although we found acute RSG administration does not affect insulin transport at the BBB, it does restore BBB vascular binding of insulin in an insulin receptor-resistant state.

Conclusions: Acute RSG treatment does not alter insulin BBB transport in healthy mice but can restore insulin receptor binding at the BBB in an insulin-resistant state.
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http://dx.doi.org/10.1002/edm2.149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375048PMC
July 2020

Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation.

Int J Mol Sci 2020 Jun 21;21(12). Epub 2020 Jun 21.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

Extracellular vesicles can cross the blood-brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB, but rates varied over 10-fold. Lipopolysaccharide (LPS), an activator of the innate immune system, enhanced uptake independently of BBB disruption for six exosomes and decreased uptake for one. Wheatgerm agglutinin (WGA) modulated transport of five exosome populations, suggesting passage by adsorptive transcytosis. Mannose 6-phosphate inhibited uptake of J774A.1, demonstrating that its BBB transporter is the mannose 6-phosphate receptor. Uptake rates, patterns, and effects of LPS or WGA were not predicted by exosome source (mouse vs. human) or cancer status of the cell lines. The cell surface proteins CD46, AVβ6, AVβ3, and ICAM-1 were variably expressed but not predictive of transport rate nor responses to LPS or WGA. A brain-to-blood efflux mechanism variably affected CNS retention and explains how CNS-derived exosomes enter blood. In summary, all exosomes tested here readily crossed the BBB, but at varying rates and by a variety of vesicular-mediated mechanisms involving specific transporters, adsorptive transcytosis, and a brain-to-blood efflux system.
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http://dx.doi.org/10.3390/ijms21124407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352415PMC
June 2020

Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury.

Sci Rep 2020 06 10;10(1):9420. Epub 2020 Jun 10.

Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.

We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. Repetitive, but not single blast exposure, induced delayed-onset BBB disruption (72 hours post-blast) in cerebellum. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) administered after blast blocked BBB disruption and prevented CD4 T-cell infiltration into cerebellum. L-NAME also blocked blast-induced increases in intercellular adhesion molecule-1 (ICAM-1), a molecule that plays a critical role in regulating blood-to-brain immune cell trafficking. Blocking NOS-mediated BBB dysfunction during this acute/subacute post-blast interval (24-71 hours after the last blast) also prevented sensorimotor impairment on a rotarod task 30 days later, long after L-NAME cleared the body. In postmortem brains from Veterans/military Servicemembers with blast-related TBI, we found marked Purkinje cell dendritic arbor structural abnormalities, which were comparable to neuropathologic findings in the blast-exposed mice. Taken collectively, these results indicate that blast provokes delayed-onset of NOS-dependent pathogenic cascades that can later emerge as behavioral dysfunction. These results also further implicate the cerebellum as a brain region vulnerable to blast-induced mTBI.
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http://dx.doi.org/10.1038/s41598-020-66113-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287110PMC
June 2020

Pituitary adenylate cyclase-activating polypeptide: Protective effects in stroke and dementia.

Peptides 2020 08 21;130:170332. Epub 2020 May 21.

Global Research Center for Innovative Life Science, Peptide Drug Innovation, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan. Electronic address:

Evidence shows that pituitary adenylate cyclase-activating polypeptide (PACAP) improves stroke outcomes and dementia. The blood-brain barrier (BBB) controls the peptide and regulatory protein exchange between the central nervous system and the blood; the transport of these regulatory substances across the BBB has been altered in animal models of stroke and Alzheimer's disease (AD). PACAP is a powerful neurotrophin that can cross the BBB, which may aid in the therapy of neurodegenerative diseases, including stroke and AD. PACAP may function as a potential drug in the treatment, prevention, or management of stroke and AD and other neurodegenerative conditions. Here, we review the effects of PACAP in studies on stroke and dementias.
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http://dx.doi.org/10.1016/j.peptides.2020.170332DOI Listing
August 2020

Comparison of the rate of dedifferentiation with increasing passages among cell sources for an in vitro model of the blood-brain barrier.

J Neural Transm (Vienna) 2020 08 7;127(8):1117-1124. Epub 2020 May 7.

Veterans Affairs Puget Sound Health Care System, Geriatric Research Education and Clinical Center, Seattle, 1660 S. Columbian Way, Seattle, WA, 98108, USA.

Cell culture-based blood-brain barrier (BBB) models are useful experimental tools for developing central nervous system drugs. Several endothelial cell sources exist for BBB models, including primary cultured brain endothelial cells and immortalized cell lines. Among them, primary cell-based models are considered suitable for the functional analysis of the BBB; however, little is known about the utility of low-passage brain endothelial cells for this purpose. In this study, we investigated the effect of passage on brain endothelial cells from human, mouse and rat brain tissue as BBB models. We established in vitro BBB models using primary brain endothelial cells (Passage 1-Passage 4) from humans, mice, and rats. To analyze the effect of cell type on BBB function, we evaluated transendothelial electrical resistance (TEER) and performed immunofluorescence staining of tight junction proteins. Among the brain endothelial cell models, TEER was highest in the Passage 1 (P1) cell-based BBB model. There was no adequate increase in TEER in other low-passage cultures (P2-P4). A confluent, non-overlapping, uniform monolayer of cells in all P1 cell-based models was visible on immunostaining of tight junction proteins, whereas it was weak or undetectable in more passaged cultures. Increasing passages cultured of brain endothelial cells did not exhibit restrictive BBB function regardless of the cell source and despite culturing with pericytes and astrocytes. Among the tested culture models, only the lowest cultured cell-based models are suitable for functional analysis of the BBB.
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http://dx.doi.org/10.1007/s00702-020-02202-1DOI Listing
August 2020

In vitro modeling of blood-brain barrier and interface functions in neuroimmune communication.

Fluids Barriers CNS 2020 Mar 30;17(1):26. Epub 2020 Mar 30.

Geriatric Research Education and Clinical Center, VA Puget Sound Healthcare System, Seattle, WA, 98108, USA.

Neuroimmune communication contributes to both baseline and adaptive physiological functions, as well as disease states. The vascular blood-brain barrier (BBB) and associated cells of the neurovascular unit (NVU) serve as an important interface for immune communication between the brain and periphery through the blood. Immune functions and interactions of the BBB and NVU in this context can be categorized into at least five neuroimmune axes, which include (1) immune modulation of BBB impermeability, (2) immune regulation of BBB transporters, secretions, and other functions, (3) BBB uptake and transport of immunoactive substances, (4) immune cell trafficking, and (5) BBB secretions of immunoactive substances. These axes may act separately or in concert to mediate various aspects of immune signaling at the BBB. Much of what we understand about immune axes has been from work conducted using in vitro BBB models, and recent advances in BBB and NVU modeling highlight the potential of these newer models for improving our understanding of how the brain and immune system communicate. In this review, we discuss how conventional in vitro models of the BBB have improved our understanding of the 5 neuroimmune axes. We further evaluate the existing literature on neuroimmune functions of novel in vitro BBB models, such as those derived from human induced pluripotent stem cells (iPSCs) and discuss their utility in evaluating aspects of neuroimmune communication.
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http://dx.doi.org/10.1186/s12987-020-00187-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106666PMC
March 2020

The Blood-Brain Barrier Interface in Diabetes Mellitus: Dysfunctions, Mechanisms and Approaches to Treatment.

Authors:
William A Banks

Curr Pharm Des 2020 ;26(13):1438-1447

Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, United States.

Diabetes mellitus (DM) is one of the most common diseases in the world. Among its effects are an increase in the risk of cognitive impairment, including Alzheimer's disease, and blood-brain barrier (BBB) dysfunction. DM is characterized by high blood glucose levels that are caused by either lack of insulin (Type I) or resistance to the actions of insulin (Type II). The phenotypes of these two types are dramatically different, with Type I animals being thin, with low levels of leptin as well as insulin, whereas Type II animals are often obese with high levels of both leptin and insulin. The best characterized change in BBB dysfunction is that of disruption. The brain regions that are disrupted, however, vary between Type I vs Type II DM, suggesting that factors other than hyperglycemia, perhaps hormonal factors such as leptin and insulin, play a regionally diverse role in BBB vulnerability or protection. Some BBB transporters are also altered in DM, including P-glycoprotein, lowdensity lipoprotein receptor-related protein 1, and the insulin transporter as other functions of the BBB, such as brain endothelial cell (BEC) expression of matrix metalloproteinases (MMPs) and immune cell trafficking. Pericyte loss secondary to the increased oxidative stress of processing excess glucose through the Krebs cycle is one mechanism that has shown to result in BBB disruption. Vascular endothelial growth factor (VEGF) induced by advanced glycation endproducts can increase the production of matrix metalloproteinases, which in turn affects tight junction proteins, providing another mechanism for BBB disruption as well as effects on P-glycoprotein. Through the enhanced expression of the redox-related mitochondrial transporter ABCB10, redox-sensitive transcription factor NF-E2 related factor-2 (Nrf2) inhibits BEC-monocyte adhesion. Several potential therapies, in addition to those of restoring euglycemia, can prevent some aspects of BBB dysfunction. Carbonic anhydrase inhibition decreases glucose metabolism and so reduces oxidative stress, preserving pericytes and blocking or reversing BBB disruption. Statins or N-acetylcysteine can reverse the BBB opening in some models of DM, fibroblast growth factor-21 improves BBB permeability through an Nrf2-dependent pathway, and nifedipine or VEGF improves memory in DM models. In summary, DM alters various aspects of BBB function through a number of mechanisms. A variety of treatments based on those mechanisms, as well as restoration of euglycemia, may be able to restore BBB functions., including reversal of BBB disruption.
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http://dx.doi.org/10.2174/1381612826666200325110014DOI Listing
November 2020
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