Blood brain barrie

Short-hairpin RNAs (shRNA), targeting knockdown of specific genes, hold enormous promise for precision-based therapeutics to treat numerous neurodegenerative disorders. However, whether shRNA constructed molecules can modify neuronal circuits underlying certain behaviors has not been explored. We designed shRNA to knockdown the human HTR2A gene in vitro using iPSC-differentiated neurons. Multi-electrode array (MEA) results showed that the knockdown of the 5HT-2A mRNA and receptor protein led to a decrease in spontaneous electrical activity...

BACKGROUND: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aβ)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25)...

Prenatal exposure to inflammation is related to the risk for cognitive impairment in offspring. However, mechanisms underlying the link between inflammatory cytokines at the maternal-fetal interface and human cognitive development are largely unknown. This study addressed this research gap by examining whether i) cytokines within the placenta are associated with different domains of neurocognitive development during infancy, and ii) if DHEA-S in cord blood mediates these associations. We also explored the role of early-life socioeconomic status (SES) in moderating the effect of fetal adrenal steroids on cognitive development in low- and middle-income country contexts...

Subarachnoid haemorrhage (SAH) can trigger a range of poorly understood cerebrovascular responses that may play a role in delayed cerebral ischemia. The brain pulse monitor is a novel non-invasive device that detects a brain photoplethysmography signal that provides information on intracranial pressure (ICP), compliance, blood flow and tissue oxygen saturation. We monitored the cerebrovascular responses in a patient with Lundberg B waves following a SAH. The patient presented with a Fischer grade 4 SAH that required urgent left posterior communicating artery aneurysm coiling and ventricular drain insertion...

Chemogenetic tools are designed to control neuronal signaling. These tools have the potential to contribute to the understanding of neuropsychiatric disorders and to the development of new treatments. One such chemogenetic technology comprises modified Pharmacologically Selective Actuator Modules (PSAMs) paired with Pharmacologically Selective Effector Molecules (PSEMs). PSAMs are receptors with ligand-binding domains that have been modified to interact only with a specific small-molecule agonist, designated a PSEM...

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an AAV capsid, BI-hTFR1, that binds human Transferrin Receptor (TfR1), a protein expressed on the blood-brain barrier (BBB). BI-hTFR1 was actively transported across a human brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in the CNS of human TFRC knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice...

BACKGROUND: Currently, there are no specific medical treatments for intracerebral haemorrhage (ICH), but the inflammatory response may provide a potential route to treatment. Given the known effects of acute brain injury on peripheral immunity, we hypothesised that inflammatory biomarkers in peripheral blood may be associated with clinical outcome following ICH, as well as perihaematomal oedema (PHO), which is an imaging marker of the neuroinflammatory response. METHODS: We searched OVID Medline and EMBASE on 07 April 2021 for studies of humans with ICH measuring an inflammatory biomarker in peripheral blood and PHO or clinical outcome...

PURPOSE: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1 and assessed its efficacy and safety alone and in combination with temozolomide (TMZ), in preclinical models. EXPERIMENTAL DESIGN: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using both subcutaneous as well as intracranial mouse xenograft models...

Resting-state functional MRI (rs-fMRI) is a popular technology that has enriched our understanding of brain and spinal cord functioning, including how different regions communicate (connectivity). But fMRI is an indirect measure of neural activity capturing blood hemodynamics. The hemodynamic response function (HRF) interfaces between the unmeasured neural activity and measured fMRI time series. The HRF is variable across brain regions and individuals, and is modulated by non-neural factors. Ignoring this HRF variability causes errors in FC estimates...

Increased use of cannabis and cannabinoids for recreational and medical purposes has led to a growth in research on their effects in animal models. The majority of this work has employed cannabinoid injections; however, smoking remains the most common route of cannabis consumption. To better model real-world cannabis use, we exposed mice to cannabis smoke to establish the pharmacokinetics of Δ9THC and its metabolites in plasma and brain. To determine the time course of Δ9THC and two major metabolites [11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (11-COOH-THC)], male and female C57BL/6J mice were exposed to smoke from sequentially burning 5 cannabis cigarettes...

INTRODUCTION: In sub-Saharan Africa (SSA), stroke is a major public health problem and the etiological aspects are poorly studied and documented because of under-medicalization; the syphilitic etiology is rarely mentioned. PATIENTS AND METHODS: We performed a retrospective study of 472 patients hospitalized for ischemic stroke between 2016 and 2021 in the Neurology Department of the University Hospital of Conakry, confirmed by neuroradiological explorations (brain CT, MRI-Angio) and a biological workup including VDRL-TPHA serological reactions in blood and CSF...

Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the temporal dynamics of neuroinflammation and metabolomics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6 J mice were exposed to wood smoke every other day for 2 weeks at an average exposure concentration of 0...

Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the aspartoacylase ( ASPA ) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid...

Viruses have evolved the ability to bind and enter cells through interactions with a wide variety of cell macromolecules. We engineered peptide-modified adeno-associated virus (AAV) capsids that transduce the brain through the introduction of de novo interactions with 2 proteins expressed on the mouse blood-brain barrier (BBB), LY6A or LY6C1. The in vivo tropisms of these capsids are predictable as they are dependent on the cell- and strain-specific expression of their target protein. This approach generated hundreds of capsids with dramatically enhanced central nervous system (CNS) tropisms within a single round of screening in vitro and secondary validation in vivo thereby reducing the use of animals in comparison to conventional multi-round in vivo selections...

The expanding field of precision gene editing using CRISPR/Cas9 has demonstrated its potential as a transformative technology in the treatment of various diseases. However, whether this genome-editing tool could be used to modify neural circuits in the central nervous system (CNS), which are implicated in complex behavioral traits, remains uncertain. In this study, we demonstrate the feasibility of noninvasive, intranasal delivery of adeno-associated virus serotype 9 (AAV9) vectors containing CRISPR/Cas9 cargo within the CNS resulting in modification of the HTR2A receptor gene...

AIMS: To identify differential expression of shorter non-coding RNA (ncRNA) genes associated with autism spectrum disorders (ASD). BACKGROUND: ncRNA are functional molecules that derive from non-translated DNA sequence. The HUGO Gene Nomenclature Committee (HGNC) have approved ncRNA gene classes with alignment to the reference human genome. One subset is microRNA (miRNA), which are highly conserved, short RNA molecules that regulate gene expression by direct post-transcriptional repression of messenger RNA...

BACKGROUND: Hyperbaric oxygen therapy (HBOT) has shown to be an effective modality in the management of variety of conditions. However, its role in traumatic brain injury (TBI) remains an area of controversy. This study aims to evaluate the safety and outcomes of HBOT in managing the long-term sequelae of TBI. METHODS: The records of TBI patients who underwent increments of 40 sessions of HBOT at 1.5 atmospheric pressure (ATA) at a single medical center were reviewed...

Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described. We enrolled patients undergoing standard-of-care resection or stereotactic biopsy for suspected intracranial tumors. Patients received peritumoral injections of 99m Tc-tilmanocept followed by planar or tomographic imaging. Fourteen patients with suspected brain tumors were enrolled. One was excluded from analysis because of tracer leakage during injection...

Nanomaterials play an increasingly important role in current medicinal practice. As one of the most significant causes of human mortality, and one that is increasing year by year, Alzheimer's disease (AD) has been the subject of a very great body of research and is an area in which nanomedicinal approaches show great promise. Dendrimers are a class of multivalent nanomaterials which can accommodate a wide range of modifications that enable them to be used as drug delivery systems. By means of suitable design, they can incorporate multiple functionalities to enable transport across the blood-brain barrier and subsequently target the diseased areas of the brain...

Recent findings have suggested that the natural compound ergothioneine (ET), which is synthesised by certain fungi and bacteria, has considerable cytoprotective potential. We previously demonstrated the anti-inflammatory effects of ET on 7-ketocholesterol (7KC)-induced endothelial injury in human blood-brain barrier endothelial cells (hCMEC/D3). 7KC is an oxidised form of cholesterol present in atheromatous plaques and the sera of patients with hypercholesterolaemia and diabetes mellitus. The aim of this study was to elucidate the protective effect of ET on 7KC-induced mitochondrial damage...