scholarly journals Manganese Dynamics in Mouse Brain After Systemic MnCl2 Administration for Activation-Induced Manganese-Enhanced MRI

2021 ◽  
Vol 15 ◽  
Author(s):  
Hiroki Tanihira ◽  
Tomonori Fujiwara ◽  
Satomi Kikuta ◽  
Noriyasu Homma ◽  
Makoto Osanai
Keyword(s):  
Control Level ◽  
Brain Parenchyma ◽  
Systemic Administration ◽  
High Concentration ◽  
Neural Activities ◽  
Enhanced Mri ◽  
Longitudinal Relaxation ◽  
Time Courses ◽  
Manganese Enhanced Mri ◽  
The Brain

Activation-induced manganese-enhanced MRI (AIM-MRI) is an attractive tool for non-invasively mapping whole brain activities. Manganese ions (Mn2+) enter and accumulate in active neurons via calcium channels. Mn2+ shortens the longitudinal relaxation time (T1) of H+, and the longitudinal relaxation rate R1 (1/T1) is proportional to Mn2+ concentration. Thus, AIM-MRI can map neural activities throughout the brain by assessing the R1 map. However, AIM-MRI is still not widely used, partially due to insufficient information regarding Mn2+ dynamics in the brain. To resolve this issue, we conducted a longitudinal study looking at manganese dynamics after systemic administration of MnCl2 by AIM-MRI with quantitative analysis. In the ventricle, Mn2+ increased rapidly within 1 h, remained high for 3 h, and returned to near control levels by 24 h after administration. Microdialysis showed that extracellular Mn returned to control levels by 4 h after administration, indicating a high concentration of extracellular Mn2+ lasts at least about 3 h after administration. In the brain parenchyma, Mn2+ increased slowly, peaked 24–48 h after administration, and returned to control level by 5 days after a single administration and by 2 weeks after a double administration with a 24-h interval. These time courses suggest that AIM-MRI records neural activity 1–3 h after MnCl2 administration, an appropriate timing of the MRI scan is in the range of 24–48 h following systemic administration, and at least an interval of 5 days or a couple of weeks for single or double administrations, respectively, is needed for a repeat AIM-MRI experiment.

scholarly journals Manganese-Enhanced MRI of the Brain in Healthy Volunteers

2019 ◽  
Vol 40 (8) ◽  
pp. 1309-1316 ◽  
Author(s):  
D.M. Sudarshana ◽  
G. Nair ◽  
J.T. Dwyer ◽  
B. Dewey ◽  
S.U. Steele ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Enhanced Mri ◽  
Manganese Enhanced Mri ◽  
The Brain

scholarly journals TrkB agonist antibody delivery to the brain using a TfR1 specific BBB shuttle provides neuroprotection in a mouse model of Parkinson’s Disease

2020 ◽  
Author(s):  
Emily Clarke ◽  
Liz Sinclair ◽  
Edward J R Fletcher ◽  
Alicja Krawczun-Rygmaczewska ◽  
Susan Duty ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Fusion Protein ◽  
Brain Parenchyma ◽  
Systemic Administration ◽  
Neurotrophin Receptor ◽  
Substantia Nigra Pars Compacta ◽  
Agonist Activity ◽  
The Brain

AbstractSingle domain shark antibodies that bind to the transferrin receptor 1 (TfR1) on brain endothelial cells can be used to shuttle antibodies and other cargos across the blood brain barrier (BBB). We have fused one of these (TXB4) to differing regions of TrkB and TrkC neurotrophin receptor agonist antibodies (AAb) and determined the effect on agonist activity, brain accumulation and engagement with neurons in the mouse brain following systemic administration. The TXB4-TrkB and TXB4-TrkC fusion proteins retain agonist activity at their respective neurotrophin receptors and in contrast to their parental AAb they rapidly accumulate in the brain reaching nM levels following a single IV injection. Following SC administration, the most active TrkB fusion protein, TXB4-TrkB1, associates with and activates ERK1/2 signalling in TrkB positive cells in the cortex and tyrosine hydroxylase (TH) positive dopaminergic neurons in the substantia nigra pars compacta (SNc). When tested in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson’s disease (PD) TXB4-TrkB1, but not the parental TrkB AAb or a TXB4-TrkC1 fusion protein, completely prevented the 6-OHDA induced death of TH positive neurons in the SNc. In conclusion, the fusion of the TXB4 TfR1 binding module allows a TrkB AAb to reach neuroprotective concentrations in the brain parenchyma following systemic administration.

scholarly journals DDEL-11. CONVECTION-ENHANCED DELIVERY OF EZH2 INHIBITOR FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii285-iii286
Author(s):  
Takahiro Sasaki ◽  
Hiroaki Katagi ◽  
Stewart Goldman ◽  
Oren Becher ◽  
Rintaro Hashizume
Keyword(s):  
Tumor Growth ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Systemic Administration ◽  
Pontine Glioma ◽  
High Concentration ◽  
Convection Enhanced Delivery ◽  
Brainstem Tumor ◽  
Animal Survival ◽  
Dismal Prognosis ◽  
The Brain

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brain tumor and the majority of patients die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities. OBJECTIVE This study aims to assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DIPG xenograft models. METHODS The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography–mass spectrometry (LC/MS). We treated mice bearing human DIPG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image and the therapeutic response was evaluated by animal survival. RESULTS LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P=0.0475). CONCLUSION Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DIPG.

scholarly journals ET-03 Convection-enhanced delivery of EZH2 inhibitor for the treatment of diffuse midline glioma

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii5-ii6
Author(s):  
Takahiro Sasaki ◽  
Hiroaki Katagi ◽  
Becker Oren ◽  
Goldman Stewart ◽  
Naoyuki Nakao ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Systemic Administration ◽  
High Concentration ◽  
Convection Enhanced Delivery ◽  
Brainstem Tumor ◽  
Animal Survival ◽  
Dismal Prognosis ◽  
Xenograft Models ◽  
The Brain ◽  
Diffuse Midline Glioma

Abstract Background: Diffuse midline glioma (DMG) is a fatal childhood brain tumor and the majority of patients die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities. Objective: This study aims to assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DMG xenograft models. Methods: The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography mass spectrometry (LC/MS). We treated mice bearing human DMG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image and the therapeutic response was evaluated by animal survival. Results: LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P = 0.0475). Conclusion: Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DMG.

Central Processing of Behaviorally Relevant Odors in the Brain of Awake Rats, as Revealed by Functional Manganese-enhanced MRI

2013 ◽  
pp. 215-220
Author(s):  
Benoist Lehallier ◽  
Olivier Rampin ◽  
Audrey Saint-Albin ◽  
Nathalie Jérôme ◽  
Christian Ouali ◽  
...  
Keyword(s):  
Central Processing ◽  
Enhanced Mri ◽  
Manganese Enhanced Mri ◽  
The Brain ◽  
Awake Rats

Reduction in cerebral arteriolar oxygen consumption by arachidonate

1985 ◽  
Vol 248 (4) ◽  
pp. H534-H539
Author(s):  
J. E. Levasseur ◽  
H. A. Kontos ◽  
E. F. Ellis
Keyword(s):  
Oxygen Consumption ◽  
Xanthine Oxidase ◽  
Brain Parenchyma ◽  
Eicosatetraenoic Acid ◽  
Cyclooxygenase Inhibitors ◽  
High Concentration ◽  
Lipoxygenase Inhibitors ◽  
Cerebral Arterioles ◽  
The Brain

The oxygen consumption of cerebral arterioles from anesthetized cats was measured using the Cartesian diver microrespirometer following in vitro incubation with 200 micrograms/ml of arachidonate or 50 micrograms/ml of 15-hydroperoxy-eicosatetraenoic acid (15-HPETE). Both agents depressed oxygen consumption severely. This effect was inhibited completely by a combination of superoxide dismutase (SOD) and catalase, indicating that it is mediated by oxygen radicals. Similar depression of oxygen consumption was observed during incubation of the vessels with xanthine oxidase and acetaldehyde as substrate. This enzymic system is known to generate superoxide and hydrogen peroxide. The effect of xanthine oxidase was also partially inhibited by SOD and catalase. The effect of arachidonate was partially inhibited by cyclooxygenase inhibitors. The effect of lipoxygenase inhibitors could not be adequately tested because they depressed oxygen consumption by themselves. Prostaglandins H2 and E2 had no effect on arteriolar oxygen consumption. The results show that arachidonate and 15-HPETE in high concentration depress cerebral arteriolar oxygen consumption via an oxygen radical-mediated mechanism. Furthermore, the radical is generated in the vessel wall and does not require either the brain parenchyma or the formed elements of the blood or the meninges for its production.

scholarly journals In vivo multi-parametric manganese-enhanced MRI for detecting amyloid plaques in rodent models of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eugene Kim ◽  
Davide Di Censo ◽  
Mattia Baraldo ◽  
Camilla Simmons ◽  
Ilaria Rosa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaques ◽  
Transgenic Animals ◽  
Surrounding Tissue ◽  
Rodent Models ◽  
Enhanced Mri ◽  
5Xfad Mice ◽  
Manganese Enhanced Mri

AbstractAmyloid plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Animals were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4 T Bruker scanner. MnCl2 improved signal-to-noise ratio but was not necessary to detect plaques in high-resolution images. Plaques were visible in all transgenic animals and no wild-types, and quantitative susceptibility mapping showed that they were more paramagnetic than the surrounding tissue. This, combined with beta-amyloid and iron staining, indicate that plaque MR visibility in both animal models was driven by plaque size and iron load. Longitudinal relaxation rate mapping revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. This was limited to the rhinencephalon in the TgF344-AD rats, while it was most significantly increased in the cortex of the 5xFAD mice. Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting amyloid plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present the first in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.

scholarly journals Genotoxic and oxidative effect of duloxetine on mouse brain and liver tissues

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Isela Álvarez-González ◽  
Scarlett Camacho-Cantera ◽  
Patricia Gómez-González ◽  
Michael J. Rendón Barrón ◽  
José A. Morales-González ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Mouse Brain ◽  
Control Level ◽  
Dna Oxidation ◽  
Methyl Methanesulfonate ◽  
Control Group ◽  
Oxidative Potential ◽  
The Brain ◽  
Oxidative Effect

AbstractWe evaluated the duloxetine DNA damaging capacity utilizing the comet assay applied to mouse brain and liver cells, as well as its DNA, lipid, protein, and nitric oxide oxidative potential in the same cells. A kinetic time/dose strategy showed the effect of 2, 20, and 200 mg/kg of the drug administered intraperitoneally once in comparison with a control and a methyl methanesulfonate group. Each parameter was evaluated at 3, 9, 15, and 21 h postadministration in five mice per group, except for the DNA oxidation that was examined only at 9 h postadministration. Results showed a significant DNA damage mainly at 9 h postexposure in both organs. In the brain, with 20 and 200 mg/kg we found 50 and 80% increase over the control group (p ≤ 0.05), in the liver, the increase of 2, 20, and 200 mg/kg of duloxetine was 50, 80, and 135% in comparison with the control level (p ≤ 0.05). DNA, lipid, protein and nitric oxide oxidation increase was also observed in both organs. Our data established the DNA damaging capacity of duloxetine even with a dose from the therapeutic range (2 mg/kg), and suggest that this effect can be related with its oxidative potential.

scholarly journals Macrophages and microglia: the cerberus of glioblastoma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Alice Buonfiglioli ◽  
Dolores Hambardzumyan
Keyword(s):  
Tumor Cells ◽  
Innate Immune System ◽  
Tumor Heterogeneity ◽  
Expression Profiles ◽  
Brain Parenchyma ◽  
Innate Immune ◽  
Malignant Growth ◽  
Neoplastic Cells ◽  
Functional Roles ◽  
The Brain

AbstractGlioblastoma (GBM) is the most aggressive and deadliest of the primary brain tumors, characterized by malignant growth, invasion into the brain parenchyma, and resistance to therapy. GBM is a heterogeneous disease characterized by high degrees of both inter- and intra-tumor heterogeneity. Another layer of complexity arises from the unique brain microenvironment in which GBM develops and grows. The GBM microenvironment consists of neoplastic and non-neoplastic cells. The most abundant non-neoplastic cells are those of the innate immune system, called tumor-associated macrophages (TAMs). TAMs constitute up to 40% of the tumor mass and consist of both brain-resident microglia and bone marrow-derived myeloid cells from the periphery. Although genetically stable, TAMs can change their expression profiles based upon the signals that they receive from tumor cells; therefore, heterogeneity in GBM creates heterogeneity in TAMs. By interacting with tumor cells and with the other non-neoplastic cells in the tumor microenvironment, TAMs promote tumor progression. Here, we review the origin, heterogeneity, and functional roles of TAMs. In addition, we discuss the prospects of therapeutically targeting TAMs alone or in combination with standard or newly-emerging GBM targeting therapies.

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