scholarly journals Assessment of Immunological Potential of Glial Restricted Progenitor Graft In Vivo-Is Immunosuppression Mandatory?

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1804
Author(s):  
Urszula Kozlowska ◽  
Aleksandra Klimczak ◽  
Karolina Anna Bednarowicz ◽  
Tomasz Zalewski ◽  
Natalia Rozwadowska ◽  
...  
Keyword(s):  
Immune Reaction ◽  
Disease Model ◽  
Immunosuppressive Drugs ◽  
Therapeutic Approaches ◽  
Stem Cell Graft ◽  
Skeletal Muscle Loss ◽  
The Brain ◽  
Privileged Site ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, causing motor neuron and skeletal muscle loss and death. One of the promising therapeutic approaches is stem cell graft application into the brain; however, an immune reaction against it creates serious limitations. This study aimed to research the efficiency of glial restricted progenitors (GRPs) grafted into murine CNS (central nervous system) in healthy models and the SOD1G93A ALS disease model. The cellular grafts were administered in semiallogenic and allogeneic settings. To investigate the models of immune reaction against grafted GRPs, we applied three immunosuppressive/immunomodulatory regimens: preimplantation factor (PiF); Tacrolimus; and CTLA-4, MR1 co-stimulatory blockade. We tracked the cells with bioluminescence imaging (BLI) in vivo to study their survival. The immune response character was evaluated with brain tissue assays and multiplex ELISA in serum and cerebrospinal fluid (CSF). The application of immunosuppressive drugs is disputable when considering cellular transplants into the immune-privileged site/brain. However, our data revealed that semiallogenic GRP graft might survive inside murine CNS without the necessity to apply any immunomodulation or immunosuppression, whereas, in the situation of allogeneic mouse setting, the combination of CTLA-4, MR1 blockade can be considered as the best immunosuppressive option.

scholarly journals Retinal correlates of neurological disorders

2019 ◽  
Vol 10 ◽  
pp. 204062231988220 ◽  
Author(s):  
Timothy E. Yap ◽  
Shiama I. Balendra ◽  
Melanie T. Almonte ◽  
M. Francesca Cordeiro
Keyword(s):  
Imaging Techniques ◽  
Prion Diseases ◽  
High Sensitivity ◽  
Cellular Level ◽  
Correct Treatment ◽  
Optical Media ◽  
Developing Area ◽  
The Brain ◽  
Lateral Sclerosis

Considering the retina as an extension of the brain provides a platform from which to study diseases of the nervous system. Taking advantage of the clear optical media of the eye and ever-increasing resolution of modern imaging techniques, retinal morphology can now be visualized at a cellular level in vivo. This has provided a multitude of possible biomarkers and investigative surrogates that may be used to identify, monitor and study diseases until now limited to the brain. In many neurodegenerative conditions, early diagnosis is often very challenging due to the lack of tests with high sensitivity and specificity, but, once made, opens the door to patients accessing the correct treatment that can potentially improve functional outcomes. Using retinal biomarkers in vivo as an additional diagnostic tool may help overcome the need for invasive tests and histological specimens, and offers the opportunity to longitudinally monitor individuals over time. This review aims to summarise retinal biomarkers associated with a range of neurological conditions including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and prion diseases from a clinical perspective. By comparing their similarities and differences according to primary pathological processes, we hope to show how retinal correlates can aid clinical decisions, and accelerate the study of this rapidly developing area of research.

MEASUREMENT OF ELEMENTAL DISTRIBUTIONS IN MOUSE BRAIN BY USING SUBMILLI-PIXE CAMERA

2010 ◽  
Vol 20 (01n02) ◽  
pp. 45-50 ◽  
Author(s):  
K. FUJIKI ◽  
S. MATSUYAMA ◽  
K. ISHII ◽  
H. YAMAZAKI ◽  
A. TERAKAWA ◽  
...  
Keyword(s):  
Mental Disease ◽  
Disease Model ◽  
Brain Slices ◽  
Physiological Role ◽  
Specific Area ◽  
Whole Brain ◽  
Model Mouse ◽  
And Control ◽  
The Brain

In a biological body, trace elements including metallic elements play important roles. Knowing their spatial distribution and amounts, we can find out some relations among a physiological role of the trace element in vivo, the function, and the disease appearance. In this study, we investigated a method to obtain elemental distributions in whole brain slice taken from mental disease model mice and control mice using in-air submilli-PIXE camera at Tohoku University. We administered 5-BrdU that was the analogue of the thymidine as a marker to detect a new born cell in especially the dentate gyrus of the hippocampus. We obtained the elemental distributions of the whole brain of subject and control mice. From elemental distributions of the brain of a mental disease model mouse, a brain contained light elements, such as P , S , Cl and K , which were uniformly distributed over the brain. Fe was accumulated in the specific area of brain. Elemental concentration of Fe was more than 10 times higher than that in the other. However, the accumulation of iron in brain slices was not observed in those of control mice. Zn is accumulated in the vicinity in hippocampus. Br was uniformly distributed over the brain. The submilli-PIXE camera will provide a powerful tool for this research.

scholarly journals Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity

2020 ◽  
Author(s):  
Laura Casares ◽  
Juan Diego Unciti ◽  
Maria Eugenia Prados ◽  
Diego Caprioglio ◽  
Maureen Higgins ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Sclerosis ◽  
Neurodegenerative Diseases ◽  
Cell Models ◽  
Therapeutic Approaches ◽  
Neuroprotective Effects ◽  
Anti Oxidant ◽  
Anti Inflammatory ◽  
The Brain

ABSTRACTOxidative stress and inflammation in the brain are two key hallmarks of neurodegenerative diseases (NDs) such as Alzheimer’s, Parkinson’s, Huntington’s and multiple sclerosis. The axis NRF2-BACH1 has anti-inflammatory and anti-oxidant properties that could be exploited pharmacologically to obtain neuroprotective effects. Activation of NRF2 or inhibition of BACH1 are, individually, promising therapeutic approaches for NDs. Compounds with dual activity as NRF2 activators and BACH1 inhibitors, could therefore potentially provide a more robust antioxidant and anti-inflammatory effects, with an overall better neuroprotective outcome. The phytocannabinoid cannabidiol (CBD) inhibits BACH1 but lacks significant NRF2 activating properties. Based on this scaffold, we have developed a novel CBD derivative that is highly effective at both inhibiting BACH1 and activating NRF2. This new CBD derivative provides neuroprotection in cell models of relevance to Huntington’s disease, setting the basis for further developments in vivo.

scholarly journals AnIn VivoMicrodialysis Study of FLZ Penetration through the Blood-Brain Barrier in Normal and 6-Hydroxydopamine Induced Parkinson’s Disease Model Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Jinfeng Hou ◽  
Qian Liu ◽  
Yingfei Li ◽  
Hua Sun ◽  
Jinlan Zhang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Model ◽  
Time Curve ◽  
Liquid Chromatography Tandem Mass ◽  
Bbb Permeability ◽  
6 Hydroxydopamine ◽  
The Brain ◽  
Active Substances

FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic squamosamide derivative and a potential anti-Parkinson’s disease (PD) agent. The objective of the present study was to investigate the penetration of free FLZ across the BBB and the effects of P-gp inhibition on FLZ transport in normal and 6-hydroxydopamine (6-OHDA) induced PD model rats.In vivomicrodialysis was used to collect FLZ containing brain and blood dialysates following intravenous (i.v.) drug administration either with or without pretreatment with the specific P-gp inhibitor, zosuquidar trihydrochloride (zosuquidar·3HCl). A sensitive, rapid, and reliable ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed and validated to quantitate free FLZ levels in the dialysates. No significant differences were observed in the brain/blood FLZ area under the concentration-time curve (AUC) ratio between normal and PD model rats. However, pretreatment with zosuquidar·3HCl markedly increased the AUC ratio in both rat models. In addition, FLZ penetration was similar in zosuquidar·3HCl-pretreated normal and PD rats. These results suggest that P-gp inhibition increases BBB permeability to FLZ, thereby supporting the hypothesis that P-gp normally restricts FLZ transfer to the brain. These findings could provide reference data for future clinical trials and may aid investigation of the BBB permeability of other CNS-active substances.

scholarly journals Glycine-alanine dipeptide repeats spread rapidly in a repeat length- and age-dependent manner in the fly brain

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Javier Morón-Oset ◽  
Tessa Supèr ◽  
Jacqueline Esser ◽  
Adrian M. Isaacs ◽  
Sebastian Grönke ◽  
...  
Keyword(s):  
Dependent Manner ◽  
Genetic Screens ◽  
Hexanucleotide Repeat ◽  
Repeat Expansions ◽  
Alanine Dipeptide ◽  
The Brain ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

AbstractHexanucleotide repeat expansions of variable size in C9orf72 are the most prevalent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense transcripts of the expansions are translated by repeat-associated non-AUG translation into five dipeptide repeat proteins (DPRs). Of these, the polyGR, polyPR and, to a lesser extent, polyGA DPRs are neurotoxic, with polyGA the most abundantly detected DPR in patient tissue. Trans-cellular transmission of protein aggregates has recently emerged as a major driver of toxicity in various neurodegenerative diseases. In vitro evidence suggests that the C9 DPRs can spread. However, whether this phenomenon occurs under more complex in vivo conditions remains unexplored. Here, we used the adult fly brain to investigate whether the C9 DPRs can spread in vivo upon expression in a subset of neurons. We found that only polyGA can progressively spread throughout the brain, which accumulates in the shape of aggregate-like puncta inside recipient cells. Interestingly, GA transmission occurred as early as 3 days after expression induction. By comparing the spread of 36, 100 and 200 polyGA repeats, we found that polyGA spread is enhanced upon expression of longer GA DPRs. Transmission of polyGA is greater in older flies, indicating that age-associated factors exacerbate the spread. These data highlight a unique propensity of polyGA to spread throughout the brain, which could contribute to the greater abundance of polyGA in patient tissue. In addition, we present a model of early GA transmission that is suitable for genetic screens to identify mechanisms of spread and its consequences in vivo.

scholarly journals Adipsin, MIP-1b, and IL-8 as CSF Biomarker Panels for ALS Diagnosis

2018 ◽  
Vol 2018 ◽  
pp. 1-5 ◽  
Author(s):  
Maria Teresa Gonzalez-Garza ◽  
Hector Ramon Martinez ◽  
Delia E. Cruz-Vega ◽  
Martin Hernandez-Torre ◽  
Jorge E. Moreno-Cuevas
Keyword(s):  
Motor Neurons ◽  
Rating Scales ◽  
Neurodegenerative Disorder ◽  
Panel Analysis ◽  
Therapeutic Approaches ◽  
Reliable Diagnosis ◽  
Als Patients ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disorder that selectively attacks motor neurons in the brain and spinal cord. Despite important advances in the knowledge of the etiology and progression of the disease, there are still no solid grounds in which a clinician could make an early objective and reliable diagnosis from which patients could benefit. Diagnosis is difficult and basically made by clinical rating scales (ALSRs and El Escorial). The possible finding of biomarkers to aid in the early diagnosis and rate of disease progression could serve for future innovative therapeutic approaches. Recently, it has been suggested that ALS has an important immune component that could represent either the cause or the consequence of the disease. In this report, we analyzed 19 different cytokines and growth factors in the cerebrospinal fluid of 77 ALS patients and 13 controls by decision tree and PanelomiX program. Results showed an increase of Adipsin, MIP-1b, and IL-6, associated with a decrease of IL-8 thresholds, related with ALS patients. This biomarker panel analysis could represent an important aid for diagnosis of ALS alongside the clinical and neurophysiological criteria.

scholarly journals Prion-Like Propagation Mechanisms in Tauopathies and Traumatic Brain Injury: Challenges and Prospects

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1487
Author(s):  
Hadeel Alyenbaawi ◽  
W. Ted Allison ◽  
Sue-Ann Mok
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Chronic Traumatic Encephalopathy ◽  
Tissue Level ◽  
Therapeutic Approaches ◽  
Tau Pathology ◽  
The Brain

The accumulation of tau protein in the form of filamentous aggregates is a hallmark of many neurodegenerative diseases such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). These dementias share traumatic brain injury (TBI) as a prominent risk factor. Tau aggregates can transfer between cells and tissues in a “prion-like” manner, where they initiate the templated misfolding of normal tau molecules. This enables the spread of tau pathology to distinct parts of the brain. The evidence that tauopathies spread via prion-like mechanisms is considerable, but work detailing the mechanisms of spread has mostly used in vitro platforms that cannot fully reveal the tissue-level vectors or etiology of progression. We review these issues and then briefly use TBI and CTE as a case study to illustrate aspects of tauopathy that warrant further attention in vivo. These include seizures and sleep/wake disturbances, emphasizing the urgent need for improved animal models. Dissecting these mechanisms of tauopathy progression continues to provide fresh inspiration for the design of diagnostic and therapeutic approaches.

scholarly journals Progress in PET Imaging of Neuroinflammation Targeting COX-2 Enzyme

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3208
Author(s):  
Jaya Prabhakaran ◽  
Andrei Molotkov ◽  
Akiva Mintz ◽  
J. John Mann
Keyword(s):  
Pet Imaging ◽  
Brain Diseases ◽  
Positron Emission ◽  
Disease Staging ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
The Brain ◽  
Lateral Sclerosis

Neuroinflammation and cyclooxygenase-2 (COX-2) upregulation are associated with the pathogenesis of degenerative brain diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, and a response to traumatic brain injury (TBI) or stroke. COX-2 is also induced in acute pain, depression, schizophrenia, various cancers, arthritis and in acute allograft rejection. Positron emission tomography (PET) imaging allows for the direct measurement of in vivo COX-2 upregulation and thereby enables disease staging, therapy evaluation and aid quantifying target occupancy of novel nonsteroidal anti-inflammatory drugs or NSAIDs. Thus far, no clinically useful radioligand is established for monitoring COX-2 induction in brain diseases due to the delay in identifying qualified COX-2-selective inhibitors entering the brain. This review examines radiolabeled COX-2 inhibitors reported in the past decade and identifies the most promising radioligands for development as clinically useful PET radioligands. Among the radioligands reported so far, the three tracers that show potential for clinical translation are, [11CTMI], [11C]MC1 and [18F]MTP. These radioligands demonstrated BBB permeablity and in vivo binding to constitutive COX-2 in the brain or induced COX-2 during neuroinflammation.

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

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