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Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer's disease.

Eur J Med Chem 2021 Apr 3;219:113426. Epub 2021 Apr 3.

Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China. Electronic address:

The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against HO (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Read More

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Inflammatory tumor microenvironment responsive neutrophil exosomes-based drug delivery system for targeted glioma therapy.

Biomaterials 2021 Mar 31;273:120784. Epub 2021 Mar 31.

School of Medicine, Chongqing University, Chongqing, 400044, China; Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China. Electronic address:

Clinical treatment of malignant glioma remains a major challenge due to high infiltrative growth and chemotherapeutic resistance of tumors and the presence of the blood brain barrier (BBB). Advanced nanoplatforms that can efficiently cross the BBB and target to brain tumor are urgently needed. Encouraged by the intrinsic inflammatory chemotaxis and excellent BBB-crossing capability of neutrophils, a bioinspired neutrophil-exosomes (NEs-Exos) system for delivering loaded doxorubicin (DOX) drug for glioma treatment is proposed and systematically investigated. Read More

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Verapamil as an Adjunct Therapy to Reduce tPA Toxicity in Hyperglycemic Stroke: Implication of TXNIP/NLRP3 Inflammasome.

Mol Neurobiol 2021 Apr 13. Epub 2021 Apr 13.

Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.

Thrombolytic therapy has remained quite challenging in hyperglycemic patients for its association with poor prognosis and increased hemorrhagic conversions. We recently showed that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin-interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, an established TXNIP inhibitor, may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption. Read More

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Terminal α2,6-sialylation of epidermal growth factor receptor modulates antibody therapy response of colorectal cancer cells.

Cell Oncol (Dordr) 2021 Apr 13. Epub 2021 Apr 13.

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal.

Background: The epidermal growth factor receptor (EGFR) is a key protein involved in cancer development. Monoclonal antibodies targeting EGFR are approved for the treatment of metastatic colorectal cancer (CRC). Despite the beneficial clinical effects observed in subgroups of patients, the acquisition of resistance to treatment remains a major concern. Read More

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Rapamycin restores brain vasculature, metabolism, and blood-brain barrier in an inflammaging model.

Geroscience 2021 Apr 13. Epub 2021 Apr 13.

Oklahoma Nathan Shock Center for Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Rapamycin (RAPA) is found to have neuro-protective properties in various neuroinflammatory pathologies, including brain aging. With magnetic resonance imaging (MRI) techniques, we investigated the effect of RAPA in a lipopolysaccharide (LPS)-induced inflammaging model in rat brains. Rats were exposed to saline (control), or LPS alone or LPS combined with RAPA treatment (via food over 6 weeks). Read More

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Transcriptomic analysis of human brain microvascular endothelial cells exposed to laminin binding protein (adhesion lipoprotein) and Streptococcus pneumoniae.

Sci Rep 2021 Apr 12;11(1):7970. Epub 2021 Apr 12.

Laboratory of Biomedical Microbiology and Immunology, University of Veterinary Medicine and Pharmacy in Kosice, Komenskeho 73, Kosice, 04181, Slovak Republic.

Streptococcus pneumoniae invades the CNS and triggers a strong cellular response. To date, signaling events that occur in the human brain microvascular endothelial cells (hBMECs), in response to pneumococci or its surface adhesins are not mapped comprehensively. We evaluated the response of hBMECs to the adhesion lipoprotein (a laminin binding protein-Lbp) or live pneumococci. Read More

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Small Interfering RNA Targeting DMP1 Protects Mice Against Blood-Brain Barrier Disruption and Brain Injury After Intracerebral Hemorrhage.

J Stroke Cerebrovasc Dis 2021 Apr 9;30(6):105760. Epub 2021 Apr 9.

Department of Anatomy, Basic Medical College, Chongqing Medical University, Chongqing 400016, China; Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China. Electronic address:

Dentin matrix protein 1 (DMP1) is an extracellular matrix phosphoprotein that is known to facilitate mineralization of collagen in bone and promote osteoblast/odontoblast differentiation. Blood-brain barrier (BBB) disruption is the major pathogenesis in secondary brain injury after intracerebral hemorrhage (ICH). This study aimed to investigate the expression pattern of DMP1 in the mouse brain and explore the role of DMP1 in BBB disruption and brain injury in a mouse model of ICH. Read More

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Intracisternal administration of tanshinone IIA-loaded nanoparticles leads to reduced tissue injury and functional deficits in a porcine model of ischemic stroke.

IBRO Neurosci Rep 2021 Jun 5;10:18-30. Epub 2021 Jan 5.

Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, United States.

Background: The absolute number of new stroke patients is annually increasing and there still remains only a few Food and Drug Administration (FDA) approved treatments with significant limitations available to patients. Tanshinone IIA (Tan IIA) is a promising potential therapeutic for ischemic stroke that has shown success in pre-clinical rodent studies but lead to inconsistent efficacy results in human patients. The physical properties of Tan-IIA, including short half-life and low solubility, suggests that Poly (lactic-co-glycolic acid) (PLGA) nanoparticle-assisted delivery may lead to improve bioavailability and therapeutic efficacy. Read More

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Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy.

Front Aging Neurosci 2021 25;13:647990. Epub 2021 Mar 25.

Geisel School of Medicine, Dartmouth College, Hanover, NH, United States.

Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Read More

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Glial Cell-Based Vascular Mechanisms and Transplantation Therapies in Brain Vessel and Neurodegenerative Diseases.

Front Cell Neurosci 2021 26;15:627682. Epub 2021 Mar 26.

Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, United States.

Neurodevelopmental and neurodegenerative diseases (NDDs) with severe neurological/psychiatric symptoms, such as cerebrovascular pathology in AD, CAA, and chronic stroke, have brought greater attention with their incidence and prevalence having markedly increased over the past few years. Causes of the significant neuropathologies, especially those observed in neurological diseases in the CNS, are commonly believed to involve multiple factors such as an age, a total environment, genetics, and an immunity contributing to their progression, neuronal, and vascular injuries. We primarily focused on the studies of glial involvement/dysfunction in part with the blood-brain barrier (BBB) and the neurovascular unit (NVU) changes, and the vascular mechanisms, which have been both suggested as critical roles in chronic stroke and many other NDDs. Read More

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Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors.

J Ginseng Res 2021 Mar 16;45(2):264-272. Epub 2019 Dec 16.

Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul, 05029, South Korea.

Background: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits and functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. Read More

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Ginseng polysaccharides: A potential neuroprotective agent.

J Ginseng Res 2021 Mar 11;45(2):211-217. Epub 2020 Sep 11.

School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, People's Republic of China.

The treatments of nervous system diseases (NSDs) have long been difficult issues for researchers because of their complexity of pathogenesis. With the advent of aging society, searching for effective treatments of NSDs has become a hot topic. Ginseng polysaccharides (GP), as the main biologically active substance in ginseng, has various biological properties in immune-regulation, anti-oxidant, anti-inflammation and etc. Read More

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Agomelatine prevents macrophage infiltration and brain endothelial cell damage in a stroke mouse model.

Aging (Albany NY) 2021 Apr 4;13. Epub 2021 Apr 4.

Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.

Background And Purpose: Ischemic/reperfusions are regarded as the clinical consensus for stroke treatment, which results in secondary injury of brain tissues. Increased blood-brain barrier (BBB) permeability and infiltration of inflammatory cells are responsible for the ischemic/reperfusion injury. In the present study, we aimed to investigate the effects of Agomelatine on brain ischemic/reperfusions injury and the underlying mechanism. Read More

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Design, synthesis, and neuroprotective effects of novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opened derivatives.

Biochem Biophys Res Commun 2021 Apr 8;556:99-105. Epub 2021 Apr 8.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, 300192, China. Electronic address:

To develop anti-ischemic stroke drugs with higher blood-brain barrier (BBB) penetrating capability and neuroprotective activity, a series of hybrid compounds containing edaravone analogue and 3-n-butylphthalide (NBP) ring-opened derivatives were synthesized and biologically evaluated. Among them, compound 10a displayed the highest protective activity in SH-SY5Y cells against oxygen and glucose deprivation (OGD) and HO insults. Experiment results indicated that 10a could inhibit platelet aggregation via the synergistic action of the edaravone analogue and NBP, and its oral administration protected the rats against ischemia/reperfusion-induced brain injury. Read More

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Design, Synthesis And In-vitro Evaluation Of Fluorinated Triazoles as Multi-Target Directed Ligands for Alzheimer Disease.

Bioorg Med Chem Lett 2021 Apr 8:127999. Epub 2021 Apr 8.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Opposite Air force Station, Palaj, Gandhinagar, Gujarat - 382355, India. Electronic address:

Alzheimer disease is multi-factorial and inflammation plays a major role in the disease progression and severity. Metals and reactive oxygen species (ROS) are the key mediators for inflammatory conditions associated with Alzheimer's. Along multi-factorial nature, major challenge for developing new drug is the ability of the molecule to cross blood brain barrier (BBB). Read More

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In vitro model for predicting the access and distribution of drugs in the brain using hCMEC/D3 cells.

Eur J Pharm Biopharm 2021 Apr 7. Epub 2021 Apr 7.

INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; CESPU - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal.

The BBB is a protective entity that prevents external substances from reaching the CNS but it also hinders the delivery of drugs into the brain when they are needed. The main objective of this work was to improve a previously proposed in vitro cell-based model by using a more physiological cell line (hCMEC/D3) to predict the main pharmacokinetic parameters that describe the access and distribution of drugs in the CNS: Kp, f, f and V. The hCMEC/D3 permeability of seven drugs was studied in transwell systems under different conditions (standard, modified with albumin and modified with brain homogenate). Read More

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Gene expression profiling of brain endothelial cells after experimental subarachnoid haemorrhage.

Sci Rep 2021 Apr 9;11(1):7818. Epub 2021 Apr 9.

Division of Neurosurgery, St. Michael's Hospital, Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.

Subarachnoid haemorrhage (SAH) is a type of hemorrhagic stroke that is associated with high morbidity and mortality. New effective treatments are needed to improve outcomes. The pathophysiology of SAH is complex and includes early brain injury and delayed cerebral ischemia, both of which are characterized by blood-brain barrier (BBB) impairment. Read More

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Longitudinal imaging of T-cells and inflammatory demyelination in a preclinical model of multiple sclerosis using F-FAraG PET and MRI.

J Nucl Med 2021 Apr 9. Epub 2021 Apr 9.

University of California San Francisco, United States.

Lymphocytes and innate immune cells are key drivers of multiple sclerosis (MS) and are the main target of MS disease modifying therapies (DMT). Ex vivo analyses of MS lesions have revealed cellular heterogeneity and variable T-cell levels, which may have important implication for patient stratification and choice of DMT. Although magnetic resonance imaging (MRI) has proven valuable to monitor DMT efficacy, its lack of specificity for cellular subtypes highlights the need for complementary methods to improve lesion characterization. Read More

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A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease.

Alzheimers Res Ther 2021 Apr 9;13(1):76. Epub 2021 Apr 9.

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia.

Background: Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer's disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. Read More

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Honokiol exerts protective effects on neural myelin sheaths after compressed spinal cord injury by inhibiting oligodendrocyte apoptosis through regulation of ER-mitochondrial interactions.

J Spinal Cord Med 2021 Apr 8:1-10. Epub 2021 Apr 8.

Medical College, China Three Gorges University, Yichang, Hubei, People's Republic of China.

Objective: To investigate the effect of honokiol on demyelination after compressed spinal cord injury (CSCI) and it's possible mechanism.

Design: Animal experiment study.

Setting: Institute of Neuroscience of Chongqing Medical University. Read More

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Synergistic neuroprotective effects of hyperbaric oxygen and methylprednisolone following contusive spinal cord injury in rat.

J Spinal Cord Med 2021 Apr 8:1-10. Epub 2021 Apr 8.

Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Objective: Recent studies revealed the neuroprotective effects of hyperbaric oxygen (HBO) on spinal cord injury (SCI). Meanwhile, the use of methylprednisolone (MP) is one of the current protocols with limited effects in SCI patients. Accordingly, the aim of the present study was to investigate the effect of combined HBO and MP treatment on SCI. Read More

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TLR4-pathway impairs synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury.

Br J Pharmacol 2021 Apr 8. Epub 2021 Apr 8.

InstitutoTeófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.

Background And Purpose: Activation of astrocytes contributes to synaptic remodelling, tissue repair and neuronal survival following traumatic brain injury (TBI). However, the mechanisms by which these cells interact to resident/infiltrated inflammatory cells to rewire neuronal networks and repair brain functions remain poorly understood. Here, we explored how TLR4-induced astrocyte activation modified synapses and cerebrovascular integrity following TBI. Read More

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An In Vitro Assay to Monitor Sertoli Cell Blood-Testis Barrier (BTB) Integrity.

Methods Mol Biol 2021 Apr 9. Epub 2021 Apr 9.

The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

In this chapter, we detail a reliable, effective, and easy to perform assay to monitor the Sertoli cell blood-testis barrier (BTB) integrity. While the BTB in the testis is composed of the tight junction (TJ) barrier and basal ES (ectoplasmic specialization, a testis-specific actin-rich adherens junction (AJ) type), this method is applicable to all other blood-tissue barrier in vitro, including endothelial TJ-barrier of the blood-brain barrier (BBB). Furthermore, this method does not require expensive set up, and can be rapidly performed by any standard biochemistry/cell biology/molecular biology laboratory. Read More

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Clarithromycin Ameliorates Early Brain Injury After Subarachnoid Hemorrhage via Suppressing Periostin-Related Pathways in Mice.

Neurotherapeutics 2021 Apr 7. Epub 2021 Apr 7.

Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan.

Subarachnoid hemorrhage (SAH) remains a life-threatening disease, and early brain injury (EBI) is an important cause of poor outcomes. The authors have reported that periostin, a matricellular protein, is one of key factors of post-SAH EBI. Clarithromycin (CAM) is a worldwide antibiotic that can inhibit periostin expression. Read More

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Efficient antiglioblastoma therapy in mice through doxorubicin-loaded nanomicelles modified using a novel brain-targeted RVG-15 peptide.

J Drug Target 2021 Apr 7:1-37. Epub 2021 Apr 7.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Glioblastoma is an aggressive malignancy and therapeutic options are limited due to the presence of the blood-brain barrier (BBB). RVG-29, a 29-amino-acid polypeptide derived from the rabies virus glycoprotein, has good drug-carrying capacity across the BBB. We reduced the size of this peptide to 15 amino acids (RVG-15), while retaining its capacity to cross the BBB. Read More

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Epigenetics in blood-brain barrier disruption.

Fluids Barriers CNS 2021 Apr 6;18(1):17. Epub 2021 Apr 6.

The Vivian L. Smith Department of Neurosurgery, University of Texas Health Science Center, 6431 Fannin St. MSB 7.147, Houston, TX, 77030, USA.

The vessels of the central nervous system (CNS) have unique barrier properties. The endothelial cells (ECs) which comprise the CNS vessels contribute to the barrier via strong tight junctions, specific transporters, and limited endocytosis which combine to protect the brain from toxins and maintains brain homeostasis. Blood-brain barrier (BBB) leakage is a serious secondary injury in various CNS disorders like stroke, brain tumors, and neurodegenerative disorders. Read More

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Delivery of oligonucleotide-based therapeutics: challenges and opportunities.

EMBO Mol Med 2021 Apr 6;13(4):e13243. Epub 2021 Apr 6.

Neuromuscular Disorders Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.

Nucleic acid-based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the field has been accelerating. To date, there are 11 marketed products based on antisense oligonucleotides, aptamers and small interfering RNAs, and many others are in the pipeline for both academia and industry. A major technology trigger for this development has been progress in oligonucleotide chemistry to improve the drug properties and reduce cost of goods, but the main hurdle for the application to a wider range of disorders is delivery to target tissues. Read More

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Exosomes secreted from sonic hedgehog-modified bone mesenchymal stem cells facilitate the repair of rat spinal cord injuries.

Acta Neurochir (Wien) 2021 Apr 5. Epub 2021 Apr 5.

Department of Spine Surgery, Guizhou Province Osteological Hospital, 123 Shachong South Street, Nanming District, Guiyang, 550002, Guizhou Province, China.

Background: Spinal cord injuries (SCIs) can cause a loss of neurons and associated sensory and motor functionality below the injured site. No approaches to treating SCIs in humans have been developed to date. Exosomes are extracellular vesicles that hold promise as a potential therapeutic modality when treating such injuries. Read More

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Numerical approach-based simulation to predict cerebrovascular shear stress in a blood-brain barrier organ-on-a-chip.

Biosens Bioelectron 2021 Mar 26;183:113197. Epub 2021 Mar 26.

Department of Mechanical Engineering, Dong-A University, Busan, 49315, Republic of Korea. Electronic address:

Most of the compounds are impermeable to the blood-brain barrier (BBB), which poses a significant challenge in the development of therapeutics for the treatment of neurological diseases. Most of the existing in vitro BBB models are not capable of mimicking the in vivo conditions and functions. The numerical approach-based simulation model was proposed to accurately predict the in vivo level shear stress for the microfluidic BBB-on-a-chip. Read More

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Neurovascular multiparametric MRI defines epileptogenic and seizure propagation regions in experimental mesiotemporal lobe epilepsy.

Epilepsia 2021 Apr 5. Epub 2021 Apr 5.

Univ. Grenoble Alpes, Grenoble Institut Neurosciences, Inserm, U1216, Grenoble 38000, France.

Objective: Improving the identification of the epileptogenic zone and associated seizure-spreading regions represents a significant challenge. Innovative brain-imaging modalities tracking neurovascular dynamics during seizures may provide new disease biomarkers.

Methods: With use of a multi-parametric magnetic resonance imaging (MRI) analysis at 9. Read More

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