WorldWideScience

Sample records for vivo brain occupancy

  1. A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies

    Energy Technology Data Exchange (ETDEWEB)

    Zeng Zhizhen [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)], E-mail: zhizhen_zeng@merck.com; O' Brien, Julie A. [Sleep and Psychiatric Disorders, Merck Research Laboratories, West Point, PA 19486 (United States); Lemaire, Wei [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); O' Malley, Stacey S.; Miller, Patricia J. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States); Zhao Zhijian [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Wallace, Michael A. [Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065 (United States); Raab, Conrad [Drug Metabolism, Merck Research Laboratories, West Point, PA 19486 (United States); Lindsley, Craig W. [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Departments of Pharmacology and Chemistry, Vanderbilt University, Nashville, TN 37232 (United States); Sur, Cyrille; Williams, David L. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)

    2008-04-15

    Introduction: In an effort to develop agents to test the NMDA hypofunction hypothesis of schizophrenia, benchmark compounds from a program to discover potent, selective, competitive glycine transporter 1 (GlyT1) inhibitors were radiolabeled in order to further study the detailed pharmacology of these inhibitors and the distribution of GlyT1 in brain. We here report the in vitro characterization of [{sup 35}S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl) ethyl)benzamide ([{sup 35}S]ACPPB), a radiotracer developed from a potent and selective non-sarcosine-derived GlyT1 inhibitor, its use in autoradiographic studies to localize (S)-2-amino-6-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl) benzamide (ACPPB) binding sites in rat and rhesus brain and for in vivo occupancy assays of competitive GlyT1 inhibitors. Methods: Functional potencies of unlabeled compounds were characterized by [{sup 14}C]glycine uptake into JAR (human placental choriocarcinoma) cells and synaptosomes. Radioligand binding studies were performed with tissue homogenates. Autoradiographic studies were performed on tissue slices. Results: ACPPB is a potent (K{sub d}=1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [{sup 35}S], is a well-behaved radioligand with low nondisplaceable binding. Autoradiographic studies of rat and rhesus brain slices with this ligand showed that specific binding sites were plentiful and nonhomogeneously distributed, with high levels of binding in the brainstem, cerebellar white matter, thalamus, cortical white matter and spinal cord gray matter. In vivo studies demonstrate displaceable binding of [{sup 35}S]ACPPB in rat brain tissues following iv administration of this radioligand. Conclusions: This is the first report of detailed anatomical localization of GlyT1 using direct radioligand binding, and the first demonstration that an in vivo occupancy assay is feasible, suggesting that it may also be feasible to develop

  2. A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies

    International Nuclear Information System (INIS)

    Zeng Zhizhen; O'Brien, Julie A.; Lemaire, Wei; O'Malley, Stacey S.; Miller, Patricia J.; Zhao Zhijian; Wallace, Michael A.; Raab, Conrad; Lindsley, Craig W.; Sur, Cyrille; Williams, David L.

    2008-01-01

    Introduction: In an effort to develop agents to test the NMDA hypofunction hypothesis of schizophrenia, benchmark compounds from a program to discover potent, selective, competitive glycine transporter 1 (GlyT1) inhibitors were radiolabeled in order to further study the detailed pharmacology of these inhibitors and the distribution of GlyT1 in brain. We here report the in vitro characterization of [ 35 S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl) ethyl)benzamide ([ 35 S]ACPPB), a radiotracer developed from a potent and selective non-sarcosine-derived GlyT1 inhibitor, its use in autoradiographic studies to localize (S)-2-amino-6-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl) benzamide (ACPPB) binding sites in rat and rhesus brain and for in vivo occupancy assays of competitive GlyT1 inhibitors. Methods: Functional potencies of unlabeled compounds were characterized by [ 14 C]glycine uptake into JAR (human placental choriocarcinoma) cells and synaptosomes. Radioligand binding studies were performed with tissue homogenates. Autoradiographic studies were performed on tissue slices. Results: ACPPB is a potent (K d =1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [ 35 S], is a well-behaved radioligand with low nondisplaceable binding. Autoradiographic studies of rat and rhesus brain slices with this ligand showed that specific binding sites were plentiful and nonhomogeneously distributed, with high levels of binding in the brainstem, cerebellar white matter, thalamus, cortical white matter and spinal cord gray matter. In vivo studies demonstrate displaceable binding of [ 35 S]ACPPB in rat brain tissues following iv administration of this radioligand. Conclusions: This is the first report of detailed anatomical localization of GlyT1 using direct radioligand binding, and the first demonstration that an in vivo occupancy assay is feasible, suggesting that it may also be feasible to develop positron emission

  3. In vivo study of drug interaction with brain benzodiazepine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, O.; Shinotoh, H.; Ito, T.; Suzuki, K.; Hashimoto, K.; Yamasaki, T.

    1985-05-01

    The possibility of direct estimation of in vivo Bz receptor occupancy in brain was evaluated using C-11, or H-3-flumazepil (Ro15-1788). In animal experiments, 1 ..mu..Ci of H-3-Ro15-1788 was injected at 0.5 or 20 hr after i.v. injection of various dosage of clonazepam. Then radioactivity in cerebral cortex, cerebellum and blood at 5 min. after injection of the tracer was compared. Competitive inhibition of in vivo binding was clearly observed when clonazepam was pretreated at 0.5 hr before injection of the tracer. On the other hand, brain radioactivity was increased when clonazepam was administered at 20 hr before injection of the tracer. This increase in binding of H-3-Ro15-1788 might be caused by rebound of Bz receptor function by treatment with Bz agonist, and this rebound may have an important role in physiological function. Clinical investigation concerning drug interaction with brain Bz receptor was performed in normal volunteer and patients with neurological disorders. The distribution of C-11-Ro15-1788 in the brain of patients chronically treated with clonazepam were significantly heterogeneous. However, cerebral blood flow estimated with N-13 NH3 of these patients were normal.

  4. Ex-vivo MR Volumetry of Human Brain Hemispheres

    Science.gov (United States)

    Kotrotsou, Aikaterini; Bennett, David A.; Schneider, Julie A.; Dawe, Robert J.; Golak, Tom; Leurgans, Sue E.; Yu, Lei; Arfanakis, Konstantinos

    2013-01-01

    Purpose The aims of this work were to: a) develop an approach for ex-vivo MR volumetry of human brain hemispheres that does not contaminate the results of histopathological examination, b) longitudinally assess regional brain volumes postmortem, and c) investigate the relationship between MR volumetric measurements performed in-vivo and ex-vivo. Methods An approach for ex-vivo MR volumetry of human brain hemispheres was developed. Five hemispheres from elderly subjects were imaged ex-vivo longitudinally. All datasets were segmented. The longitudinal behavior of volumes measured ex-vivo was assessed. The relationship between in-vivo and ex-vivo volumetric measurements was investigated in seven elderly subjects imaged both ante-mortem and postmortem. Results The presented approach for ex-vivo MR volumetry did not contaminate the results of histopathological examination. For a period of 6 months postmortem, within-subject volume variation across time points was substantially smaller than inter-subject volume variation. A close linear correspondence was detected between in-vivo and ex-vivo volumetric measurements. Conclusion Regional brain volumes measured with the presented approach for ex-vivo MR volumetry remain relatively unchanged for a period of 6 months postmortem. Furthermore, the linear relationship between in-vivo and ex-vivo MR volumetric measurements suggests that the presented approach captures information linked to ante-mortem macrostructural brain characteristics. PMID:23440751

  5. Ex vivo MR volumetry of human brain hemispheres.

    Science.gov (United States)

    Kotrotsou, Aikaterini; Bennett, David A; Schneider, Julie A; Dawe, Robert J; Golak, Tom; Leurgans, Sue E; Yu, Lei; Arfanakis, Konstantinos

    2014-01-01

    The aims of this work were to (a) develop an approach for ex vivo MR volumetry of human brain hemispheres that does not contaminate the results of histopathological examination, (b) longitudinally assess regional brain volumes postmortem, and (c) investigate the relationship between MR volumetric measurements performed in vivo and ex vivo. An approach for ex vivo MR volumetry of human brain hemispheres was developed. Five hemispheres from elderly subjects were imaged ex vivo longitudinally. All datasets were segmented. The longitudinal behavior of volumes measured ex vivo was assessed. The relationship between in vivo and ex vivo volumetric measurements was investigated in seven elderly subjects imaged both antemortem and postmortem. This approach for ex vivo MR volumetry did not contaminate the results of histopathological examination. For a period of 6 months postmortem, within-subject volume variation across time points was substantially smaller than intersubject volume variation. A close linear correspondence was detected between in vivo and ex vivo volumetric measurements. Regional brain volumes measured with this approach for ex vivo MR volumetry remain relatively unchanged for a period of 6 months postmortem. Furthermore, the linear relationship between in vivo and ex vivo MR volumetric measurements suggests that this approach captures information linked to antemortem macrostructural brain characteristics. Copyright © 2013 Wiley Periodicals, Inc.

  6. Mechanical properties of porcine brain tissue in vivo and ex vivo estimated by MR elastography.

    Science.gov (United States)

    Guertler, Charlotte A; Okamoto, Ruth J; Schmidt, John L; Badachhape, Andrew A; Johnson, Curtis L; Bayly, Philip V

    2018-03-01

    The mechanical properties of brain tissue in vivo determine the response of the brain to rapid skull acceleration. These properties are thus of great interest to the developers of mathematical models of traumatic brain injury (TBI) or neurosurgical simulations. Animal models provide valuable insight that can improve TBI modeling. In this study we compare estimates of mechanical properties of the Yucatan mini-pig brain in vivo and ex vivo using magnetic resonance elastography (MRE) at multiple frequencies. MRE allows estimations of properties in soft tissue, either in vivo or ex vivo, by imaging harmonic shear wave propagation. Most direct measurements of brain mechanical properties have been performed using samples of brain tissue ex vivo. It has been observed that direct estimates of brain mechanical properties depend on the frequency and amplitude of loading, as well as the time post-mortem and condition of the sample. Using MRE in the same animals at overlapping frequencies, we observe that porcine brain tissue in vivo appears stiffer than porcine brain tissue samples ex vivo at frequencies of 100 Hz and 125 Hz, but measurements show closer agreement at lower frequencies. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. In vivo SELEX for Identification of Brain-penetrating Aptamers

    Directory of Open Access Journals (Sweden)

    Congsheng Cheng

    2013-01-01

    Full Text Available The physiological barriers of the brain impair drug delivery for treatment of many neurological disorders. One delivery approach that has not been investigated for their ability to penetrate the brain is RNA-based aptamers. These molecules can impart delivery to peripheral tissues and circulating immune cells, where they act as ligand mimics or can be modified to carry payloads. We developed a library of aptamers and an in vivo evolution protocol to determine whether specific aptamers could be identified that would home to the brain after injection into the peripheral vasculature. Unlike biopanning with recombinant bacteriophage libraries, we found that the aptamer library employed here required more than 15 rounds of in vivo selection for convergence to specific sequences. The aptamer species identified through this approach bound to brain capillary endothelia and penetrated into the parenchyma. The methods described may find general utility for targeting various payloads to the brain.

  8. In vivo MRI of the fetal brain.

    Science.gov (United States)

    Girard, N; Raybaud, C; Dercole, C; Boubli, L; Chau, C; Cahen, S; Potier, A; Gamerre, M

    1993-01-01

    We report MRI of the brain in 45 fetuses; the findings were confirmed by pathological examination or postnatal neuroradiological studies. MRI necessitates medication to eliminate fetal motion; curare was injected into the umbilical cord, and MRI is therefore limited to cases in which umbilical cord puncture is indicated. T1-weighted images were obtained in axial, sagittal and coronal planes; the last of these were generally as the most useful as regards morphology. We demonstrated cerebral malformations (n = 13), brain haemorrhage (n = 1), a facial angioma (n = 1), a facial mass (n = 1), hydrocephalus (n = 5), unilateral ventricular enlargement (n = 1), atrophy (n = 4), a porencephalic cyst (n = 1) and normal appearances of the brain in 18 cases. Twenty-two of the fetuses were born alive, and the clinical and/or neuroradiological examination confirmed the antenatal findings. The diagnosis was also confirmed in 8 cases in which a neuropathological examination was possible.

  9. Modulating Hippocampal Plasticity with In Vivo Brain Stimulation

    Science.gov (United States)

    2016-11-17

    wires were left unhooked from stimulation device. Following stimulation , the animals were returned to their homecage until time of euthanasia and...current stimulation (tDCS) to enhance cognitive training: effect of timing of stimulation . Exp Brain Res 232:3345-3351. 15 DISTRIBUTION...AFRL-RH-WP-TR-2016-0082 MODULATING HIPPOCAMPAL PLASTICITY WITH IN-VIVO BRAIN STIMULATION Joyce G. Rohan Oakridge Institute

  10. Fusing in vivo and ex vivo NMR sources of information for brain tumor classification

    International Nuclear Information System (INIS)

    Croitor-Sava, A R; Laudadio, T; Sima, D M; Van Huffel, S; Martinez-Bisbal, M C; Celda, B; Piquer, J; Heerschap, A

    2011-01-01

    In this study we classify short echo-time brain magnetic resonance spectroscopic imaging (MRSI) data by applying a model-based canonical correlation analyses algorithm and by using, as prior knowledge, multimodal sources of information coming from high-resolution magic angle spinning (HR-MAS), MRSI and magnetic resonance imaging. The potential and limitations of fusing in vivo and ex vivo nuclear magnetic resonance sources to detect brain tumors is investigated. We present various modalities for multimodal data fusion, study the effect and the impact of using multimodal information for classifying MRSI brain glial tumors data and analyze which parameters influence the classification results by means of extensive simulation and in vivo studies. Special attention is drawn to the possibility of considering HR-MAS data as a complementary dataset when dealing with a lack of MRSI data needed to build a classifier. Results show that HR-MAS information can have added value in the process of classifying MRSI data

  11. In Vivo H MR spectroscopic imaging of human brain

    International Nuclear Information System (INIS)

    Choe, Bo Young; Suh, Tae Suk; Choi, Kyo Ho; Bahk, Yong Whee; Shinn, Kyung Sub

    1994-01-01

    To evaluate the spatial distribution of various proton metabolites in the human brain with use of water-suppressed in vivo H MR spectroscopic imaging (MRSI) technique. All of water-suppressed in vivo H MRSI were performed on 1.5 T whole-body MRI/MRS system using Stimulated Echo Acquisition Method (STEAM) Chemical Shift Imaging (CSI) pulse sequence. T1-weighted MR images were used for CSI field of view (FOV; 24 cm). Voxel size of 1.5 cm 3 was designated from the periphery of the brain which was divided by 1024 X 16 X 16 data points. Metabolite images of N-acetylaspartate (NAA), creatine/ phosphocreatine (Cr) + choline/phosphocholine (Cho), and complex of γ-aminobutyric acid (GABA) + glutamate (Glu) were obtained on the human brain. Our preliminary study suggests that in vivo H MRSI could provide the metabolite imaging to compensate for hypermetabolism on Positron Emission Tomography (PET) scans on the basis of the metabolic informations on brain tissues. The unique ability of in vivo H MRSI to offer noninvasive information about tissue biochemistry in disease states will stimulate on clinical research and disease diagnosis

  12. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    International Nuclear Information System (INIS)

    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-01-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of [ 3 H]Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in [14C]iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress [an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures], although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results

  13. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-06-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of (/sup 3/H)Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in (14C)iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress (an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures), although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results.

  14. In vivo calcium imaging of the aging and diseased brain

    International Nuclear Information System (INIS)

    Eichhoff, Gerhard; Busche, Marc A.; Garaschuk, Olga

    2008-01-01

    Over the last decade, in vivo calcium imaging became a powerful tool for studying brain function. With the use of two-photon microscopy and modern labelling techniques, it allows functional studies of individual living cells, their processes and their interactions within neuronal networks. In vivo calcium imaging is even more important for studying the aged brain, which is hard to investigate in situ due to the fragility of neuronal tissue. In this article, we give a brief overview of the techniques applicable to image aged rodent brain at cellular resolution. We use multicolor imaging to visualize specific cell types (neurons, astrocytes, microglia) as well as the autofluorescence of the ''aging pigment'' lipofuscin. Further, we illustrate an approach for simultaneous imaging of cortical cells and senile plaques in mouse models of Alzheimer's disease. (orig.)

  15. Automated Segmentation of in Vivo and Ex Vivo Mouse Brain Magnetic Resonance Images

    Directory of Open Access Journals (Sweden)

    Alize E.H. Scheenstra

    2009-01-01

    Full Text Available Segmentation of magnetic resonance imaging (MRI data is required for many applications, such as the comparison of different structures or time points, and for annotation purposes. Currently, the gold standard for automated image segmentation is nonlinear atlas-based segmentation. However, these methods are either not sufficient or highly time consuming for mouse brains, owing to the low signal to noise ratio and low contrast between structures compared with other applications. We present a novel generic approach to reduce processing time for segmentation of various structures of mouse brains, in vivo and ex vivo. The segmentation consists of a rough affine registration to a template followed by a clustering approach to refine the rough segmentation near the edges. Compared with manual segmentations, the presented segmentation method has an average kappa index of 0.7 for 7 of 12 structures in in vivo MRI and 11 of 12 structures in ex vivo MRI. Furthermore, we found that these results were equal to the performance of a nonlinear segmentation method, but with the advantage of being 8 times faster. The presented automatic segmentation method is quick and intuitive and can be used for image registration, volume quantification of structures, and annotation.

  16. In vivo detection of fluctuating brain steroid levels SHORT

    Science.gov (United States)

    Ikeda, Maaya; Rensel, Michelle A.; Schlinger, Barney A.; Remage-Healey, Luke

    2015-01-01

    This protocol describes a method for in vivo measurement of steroid hormones in brain circuits of the zebra finch. In vivo microdialysis has been used successfully to detect fluctuating neurosteroids in the auditory forebrain (Remage-Healey et al., 2008; 2012; Ikeda et al., 2012) and in the hippocampus (Rensel et al., 2012; 2013) of behaving adult zebra finches. In some cases, the steroids measured are derived locally (e.g., ‘neurosteroids’ like estrogens in males) whereas in other cases the steroids measured reflect systemic circulating levels and/or central conversion (e.g., the primary androgen testosterone and the primary glucocorticoid corticosterone). We also describe the method of reverse-microdialysis (‘retrodialysis’) of compounds that can influence local steroid neurochemistry as well as behavior. In vivo microdialysis can now be used to study steroid signaling in the brain for a variety of experimental purposes. Furthermore, similar methods have been developed to examine changing levels of catecholamines in behaving zebra finches (e.g., Sasaki et al., 2006). Thus, the combined study of neurochemistry and behavior in a vocal learning species now has a new set of powerful tools. PMID:25342066

  17. Association of brain cancer with dental x-rays and occupation in Missouri

    International Nuclear Information System (INIS)

    Neuberger, J.S.; Brownson, R.C.; Morantz, R.A.; Chin, T.D.

    1991-01-01

    This investigation of a brain cancer cluster in Missouri used two approaches to investigate associations with potential risk factors. In a case-control study in a rural town, we interviewed surrogates of cases and controls about potential risk factors. We found a statistically significant positive association of brain cancer with reported exposure to dental x-rays. Occupation was not associated with the cluster in the rural town. In a standardized proportional mortality study for the state of Missouri, we calculated the observed and expected proportion of brain cancers by occupation and industry in Missouri decedents. We found that motor vehicle manufacturers, beauty shop workers, managers and administrators, elementary school teachers, and hairdressers and cosmetologists had significantly elevated proportions of brain cancer. Brain tumors are inconsistently associated with occupation in the literature. Further study of brain cancer etiology with respect to dental x-ray exposures seems warranted

  18. Occupational therapy in patients after the brain injury with neglect syndrome

    OpenAIRE

    Říhová, Petra

    2015-01-01

    OF BACHELOR THESIS Title of bachelor thesis: Occupational therapy in patients after the brain injury with neglect syndrome This bachelor thesis is focused on summarizing the knowledge of the neglect syndrome, very interesting phenomenon accompanying brain injury. Thesis provides information about prevalence, etiopathogenesis, classification, clinical presentation and course of the disease. Special attention is devoted to diagnostic and therapeutic procedures and description of occupational th...

  19. Population-averaged macaque brain atlas with high-resolution ex vivo DTI integrated into in vivo space.

    Science.gov (United States)

    Feng, Lei; Jeon, Tina; Yu, Qiaowen; Ouyang, Minhui; Peng, Qinmu; Mishra, Virendra; Pletikos, Mihovil; Sestan, Nenad; Miller, Michael I; Mori, Susumu; Hsiao, Steven; Liu, Shuwei; Huang, Hao

    2017-12-01

    Animal models of the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate, have been irreplaceable in neurobiological studies. However, a population-averaged macaque brain diffusion tensor imaging (DTI) atlas, including comprehensive gray and white matter labeling as well as bony and facial landmarks guiding invasive experimental procedures, is not available. The macaque white matter tract pathways and microstructures have been rarely recorded. Here, we established a population-averaged macaque brain atlas with high-resolution ex vivo DTI integrated into in vivo space incorporating bony and facial landmarks, and delineated microstructures and three-dimensional pathways of major white matter tracts in vivo MRI/DTI and ex vivo (postmortem) DTI of ten rhesus macaque brains were acquired. Single-subject macaque brain DTI template was obtained by transforming the postmortem high-resolution DTI data into in vivo space. Ex vivo DTI of ten macaque brains was then averaged in the in vivo single-subject template space to generate population-averaged macaque brain DTI atlas. The white matter tracts were traced with DTI-based tractography. One hundred and eighteen neural structures including all cortical gyri, white matter tracts and subcortical nuclei, were labeled manually on population-averaged DTI-derived maps. The in vivo microstructural metrics of fractional anisotropy, axial, radial and mean diffusivity of the traced white matter tracts were measured. Population-averaged digital atlas integrated into in vivo space can be used to label the experimental macaque brain automatically. Bony and facial landmarks will be available for guiding invasive procedures. The DTI metric measurements offer unique insights into heterogeneous microstructural profiles of different white matter tracts.

  20. In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery.

    Science.gov (United States)

    Darvesh, Altaf S; Carroll, Richard T; Geldenhuys, Werner J; Gudelsky, Gary A; Klein, Jochen; Meshul, Charles K; Van der Schyf, Cornelis J

    2011-02-01

    INTRODUCTION: Microdialysis is an important in vivo sampling technique, useful in the assay of extracellular tissue fluid. The technique has both pre-clinical and clinical applications but is most widely used in neuroscience. The in vivo microdialysis technique allows measurement of neurotransmitters such as acetycholine (ACh), the biogenic amines including dopamine (DA), norepinephrine (NE) and serotonin (5-HT), amino acids such as glutamate (Glu) and gamma aminobutyric acid (GABA), as well as the metabolites of the aforementioned neurotransmitters, and neuropeptides in neuronal extracellular fluid in discrete brain regions of laboratory animals such as rodents and non-human primates. AREAS COVERED: In this review we present a brief overview of the principles and procedures related to in vivo microdialysis and detail the use of this technique in the pre-clinical measurement of drugs designed to be used in the treatment of chemical addiction, neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and as well as psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. This review offers insight into the tremendous utility and versatility of this technique in pursuing neuropharmacological investigations as well its significant potential in rational drug discovery. EXPERT OPINION: In vivo microdialysis is an extremely versatile technique, routinely used in the neuropharmacological investigation of drugs used for the treatment of neurological disorders. This technique has been a boon in the elucidation of the neurochemical profile and mechanism of action of several classes of drugs especially their effects on neurotransmitter systems. The exploitation and development of this technique for drug discovery in the near future will enable investigational new drug candidates to be rapidly moved into the clinical trial stages and to market thus providing new successful therapies for neurological diseases

  1. Brain Tissue Oxygen: In Vivo Monitoring with Carbon Paste Electrodes

    Directory of Open Access Journals (Sweden)

    John P. Lowry

    2005-11-01

    Full Text Available In this communication we review selected experiments involving the use ofcarbon paste electrodes (CPEs to monitor and measure brain tissue O2 levels in awakefreely-moving animals. Simultaneous measurements of rCBF were performed using the H2clearance technique. Voltammetric techniques used include both differential pulse (O2 andconstant potential amperometry (rCBF. Mild hypoxia and hyperoxia produced rapidchanges (decrease and increase respectively in the in vivo O2 signal. Neuronal activation(tail pinch and stimulated grooming produced similar increases in both O2 and rCBFindicating that CPE O2 currents provide an index of increases in rCBF when such increasesexceed O2 utilization. Saline injection produced a transient increase in the O2 signal whilechloral hydrate produced slower more long-lasting changes that accompanied the behavioralchanges associated with anaesthesia. Acetazolamide increased O2 levels through an increasein rCBF.

  2. In vivo mapping of brain myo-inositol.

    Science.gov (United States)

    Haris, Mohammad; Cai, Kejia; Singh, Anup; Hariharan, Hari; Reddy, Ravinder

    2011-02-01

    Myo-Inositol (MI) is one of the most abundant metabolites in the human brain located mainly in glial cells and functions as an osmolyte. The concentration of MI is altered in many brain disorders including Alzheimer's disease and brain tumors. Currently available magnetic resonance spectroscopy (MRS) methods for measuring MI are limited to low spatial resolution. Here, we demonstrate that the hydroxyl protons on MI exhibit chemical exchange with bulk water and saturation of these protons leads to reduction in bulk water signal through a mechanism known as chemical exchange saturation transfer (CEST). The hydroxyl proton exchange rate (k=600 s(-1)) is determined to be in the slow to intermediate exchange regime on the NMR time scale (chemical shift (∆ω)>k), suggesting that the CEST effect of MI (MICEST) can be imaged at high fields such as 7 T (∆ω=1.2×10(3)rad/s) and 9.4 T (∆ω=1.6×10(3) rad/s). Using optimized imaging parameters, concentration dependent broad CEST asymmetry between ~0.2 and 1.5 ppm with a peak at ~0.6 ppm from bulk water was observed. Further, it is demonstrated that MICEST detection is feasible in the human brain at ultra high fields (7 T) without exceeding the allowed limits on radiofrequency specific absorption rate. Results from healthy human volunteers (N=5) showed significantly higher (p=0.03) MICEST effect from white matter (5.2±0.5%) compared to gray matter (4.3±0.5%). The mean coefficient of variations for intra-subject MICEST contrast in WM and GM were 0.49 and 0.58 respectively. Potential overlap of CEST signals from other brain metabolites with the observed MICEST map is discussed. This noninvasive approach potentially opens the way to image MI in vivo and to monitor its alteration in many disease conditions. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. In vivo 7Li and 19F NMR studies of drugs in the brain

    International Nuclear Information System (INIS)

    Komoroski, Richard A.

    1999-01-01

    For various reasons, it is advantageous to measure the concentration of a psychoactive drug in the brain in vivo. Many drugs contain the element fluorine. Using 19 F NMR spectroscopy, we have studied the psychoactive drugs trifluoperazine and fluoxetine in the brain in vivo. Using 7 Li NMR, it is possible to detect lithium ion, used to treat manic depressive illness. We have measured the concentration and distribution of lithium in both human and rat brain in vivo. Measurement of drug levels in the human brain may provide a measure of therapeutic or toxic effects, as well as insight into drug metabolism and mechanism of action. (author)

  4. Occupational exposure to radio frequency/microwave radiation and the risk of brain tumors

    DEFF Research Database (Denmark)

    Berg, Gabriele; Spallek, Jacob; Schüz, Joachim

    2006-01-01

    It is still under debate whether occupational exposure to radio frequency/microwave electromagnetic fields (RF/MW-EMF) contributes to the development of brain tumors. This analysis examined the role of occupational RF/MW-EMF exposure in the risk of glioma and meningioma. A population-based, case....... "High" exposure was defined as an occupational exposure that may exceed the RF/MW-EMF exposure limits for the general public recommended by the International Commission on Non-Ionizing Radiation Protection. Multiple conditional logistic regressions were performed separately for glioma and meningioma...

  5. Occupational Therapy and Community Reintegration of Persons with Brain Injury

    Science.gov (United States)

    ... then help clients relearn how to do these activities (remediate) or determine new ways of accomplishing them (compensatory strategies). Through guided, graded instruction within the context of the client’s community, occupational therapy practitioners may work with individuals in real life ...

  6. Structural changes of the brain in relation to occupational stress.

    Science.gov (United States)

    Savic, Ivanka

    2015-06-01

    Despite mounting reports about the negative effects of chronic occupational stress on cognitive functions, it is still uncertain whether and how this type of stress is associated with cerebral changes. This issue was addressed in the present MRI study, in which cortical thickness (Cth) and subcortical volumes were compared between 40 subjects reporting symptoms of chronic occupational stress (38 ± 6 years) and 40 matched controls (36 ± 6 years). The degree of perceived stress was measured with Maslach Burnout Inventory. In stressed subjects, there was a significant thinning of the mesial frontal cortex. When investigating the correlation between age and Cth, the thinning effect of age was more pronounced in the stressed group in the frontal cortex. Furthermore, their amygdala volumes were bilaterally increased (P = 0.020 and P = 0.003), whereas their caudate volumes were reduced (P = 0.040), and accompanied by impaired fine motor function. The perceived stress correlated positively with the amygdala volumes (r = 0.44, P = 0.04; r = 0.43, P = 04). Occupational stress was found to be associated with cortical thinning as well as with selective changes of subcortical volumes, with behavioral correlates. The findings support the hypothesis that stress-related excitotoxicity might be an underlying mechanism, and that the described condition is a stress related illness. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Occupational risk factors for brain tumors. A case-referent death-certificate analysis

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, T.L.; Fontham, E.T.; Norman, S.A.; Stemhagen, A.; Hoover, R.N.

    1986-04-01

    Numerous studies have suggested that employment in the oil refining and chemical manufacturing industries may be associated with excess brain tumor risk. A case-referent study was undertaken to evaluate brain tumor risk by occupation and industry in three geographic areas (northern New Jersey, Philadelphia, and the Gulf Coast of Louisiana) with a heavy concentration of these industries. Seven hundred and eighteen white men dying from brain tumor at age 30 years or older were ascertained from death certificates for 1978-1981. The referents were men who died of other causes, excluding epilepsy and stroke. Usual occupation and industry were obtained from the death certificates, and the maximum likelihood estimates of the relative risk were calculated for specific industries and occupations. Small nonsignificant excess risks of brain tumors were seen among persons whose usual employment was in the petroleum refining, electrical equipment manufacturing, health services, and educational services industries. Compared with other white-collar professionals, health diagnosticians, teachers, and artists/designers had a significantly elevated brain tumor risk. Among blue-collar workers, the only group with a significantly elevated brain tumor risk was precision metal workers, who are exposed to metal dusts and fumes and substances used as coolants, lubricants, and degreasers.

  8. Occupational risk factors for brain cancer: a population-based case-control study in Iowa.

    Science.gov (United States)

    Zheng, T; Cantor, K P; Zhang, Y; Keim, S; Lynch, C F

    2001-04-01

    A number of occupations and industries have been inconsistently associated with the risk of brain cancer. To further explore possible relationships, we conducted a population-based case-control study of brain glioma in the state of Iowa, involving 375 histologically confirmed incident cases and 2434 population-based controls. Among men, the industries and/or occupations that had a significantly increased risk for employment of more than 10 years included roofing, siding, and sheet metalworking; newspaper work; rubber and plastics products, particularly tires and inner tubes; miscellaneous manufacturing industries; wholesale trade of durable goods, grain, and field beans; cleaning and building service occupations; miscellaneous mechanics and repairers; and janitors and cleaners. Subjects who worked in plumbing, heating, and air conditioning; electrical services; gasoline service stations; and military occupations also experienced a significantly increased risk. Among women, significant excess risk was observed for occupations in agricultural services and farming, apparel and textile products, electrical and electronic equipment manufacturing, various retail sales, record-keeping, and restaurant service. Workers in industries with a potential for gasoline or motor exhaust exposures experienced a non-significant excess risk of brain glioma.

  9. Occupational exposure to electromagnetic fields, leukemia and brain cancer: update of two meta-analysis

    International Nuclear Information System (INIS)

    Anon.

    2008-01-01

    This new meta-analysis found a slight increase in the risk of brain cancer and of leukemia in populations occupationally exposed to electromagnetic fields. it does not, however, support the hypothesis that electromagnetic fields have an effect on these cancers. (author)

  10. Occupational Neurobrucellosis Mimicking a Brain Tumor: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Hussein Algahtani

    2017-01-01

    Full Text Available Brucellosis is a zoonotic bacterial infection which is transmitted to humans from infected animals and is endemic in many parts of the world including Saudi Arabia. In this article, we report a case of occupational neurobrucellosis that presented with a space-occupying lesion mimicking a brain tumor. We stress on the importance of obtaining detailed social history including occupation to reach the diagnosis in several conditions including brucellosis. We also stress on taking universal precautions when handling any specimens. It may be advisable that manipulation of all unknown specimens arriving at the laboratory should occur in biological safety cabinet until a highly infectious organism is ruled out. Neurobrucellosis should be included in the differential diagnosis in patients presenting with solitary mass lesion mimicking brain tumor especially in endemic areas or high occupational risk group.

  11. Occupational and environmental risk factors of adult primary brain cancers: a systematic review.

    Science.gov (United States)

    Gomes, J; Al Zayadi, A; Guzman, A

    2011-04-01

    The incidence of brain neoplasm has been progressively increasing in recent years in the industrialized countries. One of the reasons for this increased incidence could be better access to health care and improved diagnosis in the industrialized countries. It also appears that Caucasians have a higher incidence than blacks or Hispanics or Asians. A number of risk factors have been identified and described including the genetic, ethnic and age-based factors. Certain occupational and environmental factors are also believed to influence the risk of primary adult brain tumors. Potential occupational and environmental factors include exposure to diagnostic and therapeutic radiations, electromagnetic radiation from cellular phones and other wireless devices, infectious agents, air pollution and residence near landfills and high-voltage power lines and jobs as firefighters, farmers, physician, chemists and jobs in industries such as petrochemical, power generation, synthetic rubber manufacturing, agricultural chemicals manufacturing. The purpose of this systematic review is to examine occupational and environmental risk factors of brain neoplasm. A range of occupational and environmental exposures are evaluated for significance of their relationship with adult primary brain tumors. On the basis of this review we suggest a concurrent evaluation of multiple risk factors both within and beyond occupational and environmental domains. The concurrent approach needs to consider better exposure assessment techniques, lifetime occupational exposures, genotypic and phenotypic characteristics and lifestyle and dietary habits. This approach needs to be interdisciplinary with contributions from neurologists, oncologists, epidemiologists and molecular biologists. Conclusive evidence that has eluded multitude of studies with single focus and single exposure needs to multifaceted and multidisciplinary.

  12. In vivo measurement of cadmium in an occupationally-exposed population

    International Nuclear Information System (INIS)

    Ellis, K.J.; Morgan, W.D.; Yasumura, S.; Vartsky, D.; Zanzi, I.; Cohn, S.H.

    1980-01-01

    Exposure to cadmium is recognized as a potentially serious health problem. A number of clinical abnormalities have been observed in workers occupationally exposed to cadmium. Therefore, it is essential that accurate data on body burdens be available in order to formulate dose-response relationships in man. This report describes the present Brookhaven facility for in vivo measurements of cadmium in man and recent results from a field study to a cadmium production plant. The cadmium content of the left kidney and concentration in the liver were measured by prompt-gamma neutron activation analysis in 82 occupationally exposed workers and 10 control subjects. Organ content ranged up to 57 mg in the kidney and up to 120 ppM in the liver for the industrial group. By contrast, the values for the control group ranged from 0.4 to 11.8 mg for the kidney and 0.7 to 7.9 ppM for the liver. The geometric means were 3.7 mg for the kidney and 2.7 ppM for the liver in the control group. When the data were analyzed to provide an estimate of the critical concentration for the kidney, a range of 300 to 400 μg/g for the renal cortex was calculated. These results are compared with the available data in the literature

  13. In vivo H MR spectroscopy of human brain in six normal volunteers

    International Nuclear Information System (INIS)

    Choe, Bo Young; Suh, Tae Suk; Bahk, Yong Whee; Shinn, Kyung Sub

    1993-01-01

    In vivo H MR spectroscopic studies were performed on the human brain in six normal volunteers. Some distinct proton metabolites, such as N-acetylaspartate (NAA), creatine/phosphocreatine (Cr), choline/phosphocholine (Cho), myo-inositol (Ins) and lipid (fat) were clearly identified in normal brain tissue. The signal intensity of NAA resonance is strongest. The standard ratios of metabolites from the normal brain tissue in specific regions were obtained for the references of further in vivo H MR spectroscopic studies. Our initial resulting suggest the in vivo H MR spectroscopy may provide more precise diagnosis on the basis of the metabolic information on brain tissues. The unique ability of In vivo H MR spectroscopy to offer noninvasive information about tissue biochemistry in patients will stimulate its impact on clinical research and disease diagnosis

  14. (11)C-MK-8278 PET as a tool for pharmacodynamic brain occupancy of histamine 3 receptor inverse agonists.

    Science.gov (United States)

    Van Laere, Koenraad J; Sanabria-Bohórquez, Sandra M; Mozley, David P; Burns, Donald H; Hamill, Terence G; Van Hecken, Anne; De Lepeleire, Inge; Koole, Michel; Bormans, Guy; de Hoon, Jan; Depré, Marleen; Cerchio, Kristine; Plalcza, John; Han, Lingling; Renger, John; Hargreaves, Richard J; Iannone, Robert

    2014-01-01

    The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity. Using PET and a novel high-affinity and selective radioligand (11)C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level. The mean effective dose for (11)C-MK-8278 was 5.4 ± 1.1 μSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses. (11)C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules.

  15. In vivo elemental analysis in occupational medicine using X-ray fluorescence

    International Nuclear Information System (INIS)

    Christoffersson, J.O.

    1986-01-01

    A technique for the in vivo determination of cadmium in the kidney cortex using X-ray fluorescence analysis (XRF) has been developed for clinical use. The method uses the Cd K-alfa X-rays. The radiation from the tube was polarized by scattering at 90 degrees in a plastic disc. Using a Si(Li) detector the minimum detectable concentration (MDC) of cadmium in the renal cortex was about 6 ppm for an effective dose equivalent of 3 micro-Sievert. The precision of the method was estimated to be about 23 percent. The clinical usefulness was confirmed by studying 20 occupationally exposed cadmium workers and three controls. The cadmium workers showed levels of cadmium in the kidney in the range 47-317 ppm, and controls showed levels below 30 ppm. Using XRF in vivo large-scale measurements of lead in the fingerbone of more than 100 lead workers were performed. The technique used included two 57-Co sources for excitation and a higher-purity Ge detector for the analysis of the Pb K-alfa X-rays. The MDC was about 20 ppm for an effective dose equivalent of 0.1 micro-Sievert. The precision of the method was estimated to be about 15 per cent. The in vivo measurements showed levels of fingerbone-Pb up to 148 ppm. The existence of a significant endogenous exposure from lead in the skeleton was confirmed. The fingerbone-Pb was correlated to time-integrated blood-Pb indicating that it could be used as a rough estimated of time-integrated exposure. The results from the measurements were used to develop a three-compartment (cortical bone, trabecular bone, blood/soft tissues) model. Using this model, lead levels in fingerbone, vertebrae and blood could be predicted in good agreement with observations. (author)

  16. Noninvasive photoacoustic computed tomography of mouse brain metabolism in vivo

    OpenAIRE

    Yao, Junjie; Xia, Jun; Maslov, Konstantin I.; Nasiriavanaki, Mohammadreza; Tsytsarev, Vassiliy; Demchenko, Alexei V.; Wang, Lihong V.

    2012-01-01

    We have demonstrated the feasibility of imaging mouse brain metabolism using photoacoustic computed tomography (PACT), a fast, noninvasive and functional imaging modality with optical contrast and acoustic resolution. Brain responses to forepaw stimulations were imaged transdermally and transcranially. 2-NBDG, which diffuses well across the blood–brain-barrier, provided exogenous contrast for photoacoustic imaging of glucose response. Concurrently, hemoglobin provided endogenous contrast for ...

  17. Effect of cadmium on lipid metabolism of brain. In vivo incorporation of labelled acetate into lipids

    Energy Technology Data Exchange (ETDEWEB)

    Gulati, S; Gill, K D; Nath, R

    1987-01-01

    The effect of early postnatal cadmium exposure on the in vivo incorporation of (1-/sup 14/C) sodium acetate into various lipid classes of the weanling rat brain was studied. A stimulated incorporation of the label was observed in total lipids, phospholipids, cholesterol, cerebrosides and sulphatides of the brain of Cd-exposed animals compared to controls.

  18. In vivo deep brain imaging of rats using oral-cavity illuminated photoacoustic computed tomography

    Science.gov (United States)

    Lin, Li; Xia, Jun; Wong, Terence T. W.; Zhang, Ruiying; Wang, Lihong V.

    2015-03-01

    We demonstrate, by means of internal light delivery, photoacoustic imaging of the deep brain of rats in vivo. With fiber illumination via the oral cavity, we delivered light directly into the bottom of the brain, much more than can be delivered by external illumination. The study was performed using a photoacoustic computed tomography (PACT) system equipped with a 512-element full-ring transducer array, providing a full two-dimensional view aperture. Using internal illumination, the PACT system provided clear cross sectional photoacoustic images from the palate to the middle brain of live rats, revealing deep brain structures such as the hypothalamus, brain stem, and cerebral medulla.

  19. Brain Serotonin Transporter Occupancy by Oral Sibutramine Dosed to Steady State: A PET Study Using 11C-DASB in Healthy Humans

    Science.gov (United States)

    Talbot, Peter S; Bradley, Stefan; Clarke, Cyril P; Babalola, Kola O; Philipp, Andrew W; Brown, Gavin; McMahon, Adam W; Matthews, Julian C

    2010-01-01

    Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15 mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. 11C-DASB PET scans were performed on the HRRT camera. Binding potentials (BPND) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30±10%), was similar across brain regions, but varied widely across subjects (15–46%). Occupancy was correlated positively (p=0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at sibutramine is of modest magnitude and may be mediated predominantly by M2 in humans. 5-HT reuptake inhibition may be necessary but is not sufficient for sibutramine's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and NET. PMID:19890256

  20. Development of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury

    Science.gov (United States)

    2016-02-01

    excised after severe brain injury . Experimental neurology 2004;190:192-203. 24. Frost B, Diamond MI. Prion-like mechanisms in neurodegenerative...Brain Injury PRINCIPAL INVESTIGATORs: Marc Diamond, MD CONTRACTING ORGANIZATION: Washington University, St Louis MO 63110 UT Southwestern, Dallas...of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury 5b. GRANT NUMBER W81XWH-13-2-0016 5c. PROGRAM ELEMENT NUMBER 6

  1. Occupational exposure to extremely low frequency magnetic fields and brain tumour risks in the INTEROCC study

    Science.gov (United States)

    Turner, Michelle C; Benke, Geza; Bowman, Joseph D; Figuerola, Jordi; Fleming, Sarah; Hours, Martine; Kincl, Laurel; Krewski, Daniel; McLean, Dave; Parent, Marie-Elise; Richardson, Lesley; Sadetzki, Siegal; Schlaefer, Klaus; Schlehofer, Brigitte; Schüz, Joachim; Siemiatycki, Jack; van Tongeren, Martie; Cardis, Elisabeth

    2014-01-01

    Background Occupational exposure to extremely low frequency magnetic fields (ELF) is a suspected risk factor for brain tumours, however the literature is inconsistent. Few studies have assessed whether ELF in different time windows of exposure may be associated with specific histologic types of brain tumours. This study examines the association between ELF and brain tumours in the large-scale INTEROCC study. Methods Cases of adult primary glioma and meningioma were recruited in seven countries (Australia, Canada, France, Germany, Israel, New Zealand, United Kingdom) between 2000 and 2004. Estimates of mean workday ELF exposure based on a job exposure matrix assigned. Estimates of cumulative exposure, average exposure, maximum exposure, and exposure duration were calculated for the lifetime, and 1–4, 5–9, and 10+ years prior to the diagnosis/reference date. Results There were 3,761 included brain tumour cases (1,939 glioma, 1,822 meningioma) and 5,404 population controls. There was no association between lifetime cumulative ELF exposure and glioma or meningioma risk. However, there were positive associations between cumulative ELF 1–4 years prior to the diagnosis/reference date and glioma (odds ratio (OR) ≥ 90th percentile vs Occupational ELF exposure may play a role in the later stages (promotion and progression) of brain tumourigenesis. PMID:24935666

  2. Noninvasive photoacoustic computed tomography of mouse brain metabolism in vivo

    Science.gov (United States)

    Yao, Junjie; Xia, Jun; Maslov, Konstantin I.; Nasiriavanaki, Mohammadreza; Tsytsarev, Vassiliy; Demchenko, Alexei V.; Wang, Lihong V.

    2012-01-01

    We have demonstrated the feasibility of imaging mouse brain metabolism using photoacoustic computed tomography (PACT), a fast, noninvasive and functional imaging modality with optical contrast and acoustic resolution. Brain responses to forepaw stimulations were imaged transdermally and transcranially. 2-NBDG, which diffuses well across the blood-brain-barrier, provided exogenous contrast for photoacoustic imaging of glucose response. Concurrently, hemoglobin provided endogenous contrast for photoacoustic imaging of hemodynamic response. Glucose and hemodynamic responses were quantitatively decoupled by using two-wavelength measurements. We found that glucose uptake and blood perfusion around the somatosensory region of the contralateral hemisphere were both increased by stimulations, indicating elevated neuron activity. While the glucose response area was more homogenous and confined within the somatosensory region, the hemodynamic response area had a clear vascular pattern and spread wider than the somatosensory region. Our results demonstrate that 2-NBDG-enhanced PACT is a promising tool for noninvasive studies of brain metabolism. PMID:22940116

  3. Noninvasive photoacoustic computed tomography of mouse brain metabolism in vivo

    Science.gov (United States)

    Yao, Junjie; Xia, Jun; Maslov, Konstantin; Avanaki, Mohammadreza R. N.; Tsytsarev, Vassiliy; Demchenko, Alexei V.; Wang, Lihong V.

    2013-03-01

    To control the overall action of the body, brain consumes a large amount of energy in proportion to its volume. In humans and many other species, the brain gets most of its energy from oxygen-dependent metabolism of glucose. An abnormal metabolic rate of glucose and/or oxygen usually reflects a diseased status of brain, such as cancer or Alzheimer's disease. We have demonstrated the feasibility of imaging mouse brain metabolism using photoacoustic computed tomography (PACT), a fast, noninvasive and functional imaging modality with optical contrast and acoustic resolution. Brain responses to forepaw stimulations were imaged transdermally and transcranially. 2-NBDG, which diffuses well across the blood-brain-barrier, provided exogenous contrast for photoacoustic imaging of glucose response. Concurrently, hemoglobin provided endogenous contrast for photoacoustic imaging of hemodynamic response. Glucose and hemodynamic responses were quantitatively unmixed by using two-wavelength measurements. We found that glucose uptake and blood perfusion around the somatosensory region of the contralateral hemisphere were both increased by stimulations, indicating elevated neuron activity. The glucose response amplitude was about half that of the hemodynamic response. While the glucose response area was more homogenous and confined within the somatosensory region, the hemodynamic response area showed a clear vascular pattern and spread about twice as wide as that of the glucose response. The PACT of mouse brain metabolism was validated by high-resolution open-scalp OR-PAM and fluorescence imaging. Our results demonstrate that 2-NBDG-enhanced PACT is a promising tool for noninvasive studies of brain metabolism.

  4. Optical coherence tomography imaging of cranial meninges post brain injury in vivo

    Institute of Scientific and Technical Information of China (English)

    Woo June Choi; Ruikang K.Wang

    2017-01-01

    We report a new application of optical coherence tomography (OCT) to investigate the cranial meninges in an animal model of brain injury in vivo.The injury is induced in a mouse due to skull thinning,in which the repeated and excessive drilling exerts mechanical stress on the mouse brain through the skull,resulting in acute and mild brain injury.Transcranial OCT imaging reveals an interesting virtual space between the cranial meningeal layers post skull thinning,which is gradually closed within hours.The finding suggests a promise of OCT as an effective tool to monitor the mechanical trauma in the small animal model of brain injury.

  5. Confocal laser endomicroscopy for diagnosis and histomorphologic imaging of brain tumors in vivo.

    Directory of Open Access Journals (Sweden)

    Sebastian Foersch

    Full Text Available Early detection and evaluation of brain tumors during surgery is crucial for accurate resection. Currently cryosections during surgery are regularly performed. Confocal laser endomicroscopy (CLE is a novel technique permitting in vivo histologic imaging with miniaturized endoscopic probes at excellent resolution. Aim of the current study was to evaluate CLE for in vivo diagnosis in different types and models of intracranial neoplasia. In vivo histomorphology of healthy brains and two different C6 glioma cell line allografts was evaluated in rats. One cell line expressed EYFP, the other cell line was used for staining with fluorescent dyes (fluorescein, acriflavine, FITC-dextran and Indocyanine green. To evaluate future application in patients, fresh surgical resection specimen of human intracranial tumors (n = 15 were examined (glioblastoma multiforme, meningioma, craniopharyngioma, acoustic neurinoma, brain metastasis, medulloblastoma, epidermoid tumor. Healthy brain tissue adjacent to the samples served as control. CLE yielded high-quality histomorphology of normal brain tissue and tumors. Different fluorescent agents revealed distinct aspects of tissue and cell structure (nuclear pattern, axonal pathways, hemorrhages. CLE discrimination of neoplastic from healthy brain tissue was easy to perform based on tissue and cellular architecture and resemblance with histopathology was excellent. Confocal laser endomicroscopy allows immediate in vivo imaging of normal and neoplastic brain tissue at high resolution. The technology might be transferred to scientific and clinical application in neurosurgery and neuropathology. It may become helpful to screen for tumor free margins and to improve the surgical resection of malignant brain tumors, and opens the door to in vivo molecular imaging of tumors and other neurologic disorders.

  6. In vivo electrical conductivity imaging of a canine brain using a 3 T MREIT system

    International Nuclear Information System (INIS)

    Kim, Hyung Joong; Oh, Tong In; Kim, Young Tae; Lee, Byung Il; Woo, Eung Je; Lee, Soo Yeol; Seo, Jin Keun; Kwon, Ohin; Park, Chunjae; Kang, Byeong Teck; Park, Hee Myung

    2008-01-01

    Magnetic resonance electrical impedance tomography (MREIT) aims at producing high-resolution cross-sectional conductivity images of an electrically conducting object such as the human body. Following numerous phantom imaging experiments, the most recent study demonstrated successful conductivity image reconstructions of postmortem canine brains using a 3 T MREIT system with 40 mA imaging currents. Here, we report the results of in vivo animal imaging experiments using 5 mA imaging currents. To investigate any change of electrical conductivity due to brain ischemia, canine brains having a regional ischemic model were scanned along with separate scans of canine brains having no disease model. Reconstructed multi-slice conductivity images of in vivo canine brains with a pixel size of 1.4 mm showed a clear contrast between white and gray matter and also between normal and ischemic regions. We found that the conductivity value of an ischemic region decreased by about 10–14%. In a postmortem brain, conductivity values of white and gray matter decreased by about 4–8% compared to those in a live brain. Accumulating more experience of in vivo animal imaging experiments, we plan to move to human experiments. One of the important goals of our future work is the reduction of the imaging current to a level that a human subject can tolerate. The ability to acquire high-resolution conductivity images will find numerous clinical applications not supported by other medical imaging modalities. Potential applications in biology, chemistry and material science are also expected

  7. [18F]haloperidol binding in baboon brain in vivo

    International Nuclear Information System (INIS)

    Yousef, Khalil A.; Fowler, Joanna S.; Volkow, Nora D.; Dewey, Stephen L.; Shea, Colleen; Schlyer, David J.; Gatley, S. John; Logan, Jean; Wolf, Alfred P.

    1996-01-01

    The binding of [ 18 F]haloperidol to dopamine D2 and to sigma recognition sites in baboon brain was examined using positron emission tomography (PET). Studies were performed at baseline and after treatment with either haloperidol (to evaluate saturability), (+)-butaclamol (which has specificity for dopamine D2 receptors) or (-)-butaclamol (which has specificity for sigma sites). Binding was widespread. Treatment with (-)-butaclamol had no effect, whereas (+)-butaclamol selectively reduced the uptake in striatum. Haloperidol increased the clearance rate from all brain regions. These results indicate that the binding profile of [ 18 F]haloperidol does not permit the selective examination of either dopamine D2 or sigma sites using PET

  8. Targeting neurotransmitter receptors with nanoparticles in vivo allows single-molecule tracking in acute brain slices

    Science.gov (United States)

    Varela, Juan A.; Dupuis, Julien P.; Etchepare, Laetitia; Espana, Agnès; Cognet, Laurent; Groc, Laurent

    2016-03-01

    Single-molecule imaging has changed the way we understand many biological mechanisms, particularly in neurobiology, by shedding light on intricate molecular events down to the nanoscale. However, current single-molecule studies in neuroscience have been limited to cultured neurons or organotypic slices, leaving as an open question the existence of fast receptor diffusion in intact brain tissue. Here, for the first time, we targeted dopamine receptors in vivo with functionalized quantum dots and were able to perform single-molecule tracking in acute rat brain slices. We propose a novel delocalized and non-inflammatory way of delivering nanoparticles (NPs) in vivo to the brain, which allowed us to label and track genetically engineered surface dopamine receptors in neocortical neurons, revealing inherent behaviour and receptor activity regulations. We thus propose a NP-based platform for single-molecule studies in the living brain, opening new avenues of research in physiological and pathological animal models.

  9. Enhanced insulin binding to blood-brain barrier in vivo and to brain microvessels in vitro in newborn rabbits

    International Nuclear Information System (INIS)

    Frank, H.J.; Jankovic-Vokes, T.; Pardridge, W.M.; Morris, W.L.

    1985-01-01

    Insulin is a known growth factor in nonneural tissue, and recent studies have shown that there are insulin receptors throughout the adult and fetal central nervous system. Since insulin has only limited access to the adult brain, this study was undertaken to determine if insulin has increased availability to the newborn brain where it may act as a neonatal brain growth promoter. In vivo brain uptake of 125 I-insulin after a single-pass carotid injection was measured in newborn, 3-wk-old and 11-wk-old (adult) rabbits. The brain uptake index (BUI) relative to a 3 HOH reference was 22.0 +/- 1.1% (mean +/- SEM) for newborn, 12.8 +/- 0.6% for 3-wk-old, and 6.5 +/- 0.1% for adults. Specific 125 I-insulin binding to isolated cerebral microvessels was similarly increased in the newborn compared with the 3-wk-old and adult animals. Scatchard analysis revealed that the difference was due to an increase in receptor number with only minimal changes in the affinity. The increased availability of circulating insulin to the newborn brain was further corroborated by elevated CSF/serum and brain/serum insulin ratios in the newborn versus adult. These results suggest that insulin has increased access to the newborn brain where it may function as a growth factor

  10. SPECT and PET Serve as Molecular Imaging Techniques and in Vivo Biomarkers for Brain Metastases

    Science.gov (United States)

    Palumbo, Barbara; Buresta, Tommaso; Nuvoli, Susanna; Spanu, Angela; Schillaci, Orazio; Fravolini, Mario Luca; Palumbo, Isabella

    2014-01-01

    Nuclear medicine techniques (single photon emission computerized tomography, SPECT, and positron emission tomography, PET) represent molecular imaging tools, able to provide in vivo biomarkers of different diseases. To investigate brain tumours and metastases many different radiopharmaceuticals imaged by SPECT and PET can be used. In this review the main and most promising radiopharmaceuticals available to detect brain metastases are reported. Furthermore the diagnostic contribution of the combination of SPECT and PET data with radiological findings (magnetic resonance imaging, MRI) is discussed. PMID:24897023

  11. Pharmacologic Effects in vivo in Brain by Vector-Mediated Peptide Drug Delivery

    Science.gov (United States)

    Bickel, Ulrich; Yoshikawa, Takayoshi; Landaw, Elliot M.; Faull, Kym F.; Pardridge, William M.

    1993-04-01

    Pharmacologic effects in brain caused by systemic administration of neuropeptides are prevented by poor transport of the peptide through the brain vascular endothelium, which comprises the blood-brain barrier in vivo. In the present study, successful application of a chimeric peptide approach to enhance drug delivery through the blood-brain barrier for the purpose of achieving a central nervous system pharmacologic effect is described. The chimeric peptide was formed by linkage of a potent vasoactive intestinal peptide (VIP) analogue, which had been monobiotinylated, to a drug transport vector. The vector consisted of a covalent conjugate of avidin and the OX26 monoclonal antibody to the transferrin receptor. Owing to the high concentration of transferrin receptors on brain capillary endothelia, OX26 targets brain and undergoes receptor-mediated transcytosis through the blood-brain barrier. Systemic infusion of low doses (12 μg/kg) of the VIP chimeric peptide in rats resulted in an in vivo central nervous system pharmacologic effect: a 65% increase in cerebral blood flow. Biotinylated VIP analogue without the brain transport vector was ineffective.

  12. Recent Methods for Measuring Dopamine D3 receptor Occupancy In Vivo: Importance for Drug Development

    Directory of Open Access Journals (Sweden)

    Bernard eLe Foll

    2014-07-01

    Full Text Available There is considerable interest in developing highly selective dopamine D3 receptor ligands for a variety of mental health disorders. Dopamine D3 receptors have been implicated in Parkinson’s Disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10-15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from preclinical studies. Recently, with the advent of [11C]-(+-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [11C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [11C]-(+-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [11C]-(+-PHNO binding by region of interest. This novel methodology can be used in preclinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [11C]-(+-PHNO can provide insights into the function of D3 receptors in addiction is also presented.

  13. Estimation of in-vivo neurotransmitter release by brain microdialysis: the issue of validity.

    Science.gov (United States)

    Di Chiara, G.; Tanda, G.; Carboni, E.

    1996-11-01

    Although microdialysis is commonly understood as a method of sampling low molecular weight compounds in the extracellular compartment of tissues, this definition appears insufficient to specifically describe brain microdialysis of neurotransmitters. In fact, transmitter overflow from the brain into dialysates is critically dependent upon the composition of the perfusing Ringer. Therefore, the dialysing Ringer not only recovers the transmitter from the extracellular brain fluid but is a main determinant of its in-vivo release. Two types of brain microdialysis are distinguished: quantitative micro-dialysis and conventional microdialysis. Quantitative microdialysis provides an estimate of neurotransmitter concentrations in the extracellular fluid in contact with the probe. However, this information might poorly reflect the kinetics of neurotransmitter release in vivo. Conventional microdialysis involves perfusion at a constant rate with a transmitter-free Ringer, resulting in the formation of a steep neurotransmitter concentration gradient extending from the Ringer into the extracellular fluid. This artificial gradient might be critical for the ability of conventional microdialysis to detect and resolve phasic changes in neurotransmitter release taking place in the implanted area. On the basis of these characteristics, conventional microdialysis of neurotransmitters can be conceptualized as a model of the in-vivo release of neurotransmitters in the brain. As such, the criteria of face-validity, construct-validity and predictive-validity should be applied to select the most appropriate experimental conditions for estimating neurotransmitter release in specific brain areas in relation to behaviour.

  14. In vivo binding of tritiated dopaminergic ligands in mouse brain

    International Nuclear Information System (INIS)

    Baudry, Michel; Martres, M.-P.; Le Sellin, Michel; Schwartz, J.-C.; Guyon, Anne; Morgat, J.-L.

    1977-01-01

    The regional distribution of various dopaminergic radiolabelled ligands has been studied in the mouse brain after their intravenous injections. Among them, 3 H-pimozide and, to a lesser extent, 3 H-apomorphine are preferentially accumulated in the striatum, a region rich in dopaminergic receptors, as compared to cerebellum, a region believed not to contain dopaminergic receptors. For 3 H-pimozide, this preferential retention is due to a more rapid disappearance from the cerebellum than from the striatum. Moreover, prior administration of various neuroleptics which do not modify 3 H-pimozide levels recovered in the cerebellum, abolishes the differential retention of 3 H-pimozide in the striatum. These results indicate that the retention of 3 H-pimozide in the brain may be regarded as the sum of two components: a non-specific retention evaluated by 3 H-pimozide level in the cerebellum and the binding to dopaminergic receptors [fr

  15. Adaptive optical microscope for brain imaging in vivo

    Science.gov (United States)

    Wang, Kai

    2017-04-01

    The optical heterogeneity of biological tissue imposes a major limitation to acquire detailed structural and functional information deep in the biological specimens using conventional microscopes. To restore optimal imaging performance, we developed an adaptive optical microscope based on direct wavefront sensing technique. This microscope can reliably measure and correct biological samples induced aberration. We demonstrated its performance and application in structural and functional brain imaging in various animal models, including fruit fly, zebrafish and mouse.

  16. Guidelines to PET measurements of the target occupancy in the brain for drug development

    Energy Technology Data Exchange (ETDEWEB)

    Takano, Akihiro; Varrone, Andrea; Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Stockholm (Sweden); Salvadori, Piero [CNR Istituto di Fisiologia Clinica, Pisa (Italy); Gee, Antony [Kings College London, Department of Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Windhorst, Albert; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Vercouillie, Johnny [Universite Francois Rabelais de Tours, UMR Inserm U930, Tours (France); Bormans, Guy [KU Leuven, Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Leuven (Belgium)

    2016-11-15

    This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations. (orig.)

  17. Optical microangiography enabling visualization of change in meninges after traumatic brain injury in mice in vivo

    Science.gov (United States)

    Choi, Woo June; Qin, Wan; Qi, Xiaoli; Wang, Ruikang K.

    2016-03-01

    Traumatic brain injury (TBI) is a form of brain injury caused by sudden impact on brain by an external mechanical force. Following the damage caused at the moment of injury, TBI influences pathophysiology in the brain that takes place within the minutes or hours involving alterations in the brain tissue morphology, cerebral blood flow (CBF), and pressure within skull, which become important contributors to morbidity after TBI. While many studies for the TBI pathophysiology have been investigated with brain cortex, the effect of trauma on intracranial tissues has been poorly studied. Here, we report use of high-resolution optical microangiography (OMAG) to monitor the changes in cranial meninges beneath the skull of mouse after TBI. TBI is induced on a brain of anesthetized mouse by thinning the skull using a soft drill where a series of drilling exert mechanical stress on the brain through the skull, resulting in mild brain injury. Intracranial OMAG imaging of the injured mouse brain during post-TBI phase shows interesting pathophysiological findings in the meningeal layers such as widening of subdural space as well as vasodilation of subarachnoid vessels. These processes are acute and reversible within hours. The results indicate potential of OMAG to explore mechanism involved following TBI on small animals in vivo.

  18. In vivo multiphoton tomography and fluorescence lifetime imaging of human brain tumor tissue.

    Science.gov (United States)

    Kantelhardt, Sven R; Kalasauskas, Darius; König, Karsten; Kim, Ella; Weinigel, Martin; Uchugonova, Aisada; Giese, Alf

    2016-05-01

    High resolution multiphoton tomography and fluorescence lifetime imaging differentiates glioma from adjacent brain in native tissue samples ex vivo. Presently, multiphoton tomography is applied in clinical dermatology and experimentally. We here present the first application of multiphoton and fluorescence lifetime imaging for in vivo imaging on humans during a neurosurgical procedure. We used a MPTflex™ Multiphoton Laser Tomograph (JenLab, Germany). We examined cultured glioma cells in an orthotopic mouse tumor model and native human tissue samples. Finally the multiphoton tomograph was applied to provide optical biopsies during resection of a clinical case of glioblastoma. All tissues imaged by multiphoton tomography were sampled and processed for conventional histopathology. The multiphoton tomograph allowed fluorescence intensity- and fluorescence lifetime imaging with submicron spatial resolution and 200 picosecond temporal resolution. Morphological fluorescence intensity imaging and fluorescence lifetime imaging of tumor-bearing mouse brains and native human tissue samples clearly differentiated tumor and adjacent brain tissue. Intraoperative imaging was found to be technically feasible. Intraoperative image quality was comparable to ex vivo examinations. To our knowledge we here present the first intraoperative application of high resolution multiphoton tomography and fluorescence lifetime imaging of human brain tumors in situ. It allowed in vivo identification and determination of cell density of tumor tissue on a cellular and subcellular level within seconds. The technology shows the potential of rapid intraoperative identification of native glioma tissue without need for tissue processing or staining.

  19. The in vivo phosphorylation sites of rat brain dynamin I

    DEFF Research Database (Denmark)

    Graham, Mark E; Anggono, Victor; Bache, Nicolai

    2007-01-01

    -824). To resolve the discrepancy and to better understand the biological roles of dynI phosphorylation, we undertook a systematic identification of all phosphorylation sites in rat brain nerve terminal dynI. Using phosphoamino acid analysis, exclusively phospho-serine residues were found. Thr(780) phosphorylation...... of their relative abundance and relative responses to depolarization. The multiple phospho-sites suggest subtle regulation of synaptic vesicle endocytosis by new protein kinases and new protein-protein interactions. The homologous dynI and dynIII phosphorylation indicates a high mechanistic similarity. The results...

  20. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System

    DEFF Research Database (Denmark)

    Beliveau, Vincent; Ganz-Benjaminsen, Melanie; Feng, Ling

    2017-01-01

    The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4...... with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human...... brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system...

  1. Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.

    Directory of Open Access Journals (Sweden)

    Takeaki Saijo

    Full Text Available A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT(1A receptor, called Wf-516 (structural formula: (2S-1-[4-(3,4-dichlorophenylpiperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-ylbenzo[b]furan-4-yloxy]propan-2-ol monohydrochloride, has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT(1A receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT(1A receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT(1A receptors. In addition, [(35S]guanosine 5'-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT(1A receptors. This finding has lent support to reports that diverse partial agonists for 5-HT(1A receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

  2. Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.

    Science.gov (United States)

    Saijo, Takeaki; Maeda, Jun; Okauchi, Takashi; Maeda, Jun-ichi; Morio, Yasunori; Kuwahara, Yasuhiro; Suzuki, Masayuki; Goto, Nobuharu; Fukumura, Toshimitsu; Suhara, Tetsuya; Higuchi, Makoto

    2012-01-01

    A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT(1A)) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT(1A) receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT(1A) receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT(1A) receptors. In addition, [(35)S]guanosine 5'-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT(1A) receptors. This finding has lent support to reports that diverse partial agonists for 5-HT(1A) receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

  3. 2.5D Representations Combining in vivo 3D MRI and ex vivo 2D MSI Approaches to Study the Lipid Distribution in the Whole Sheep Brain

    OpenAIRE

    Labas , Valérie; Teixeira-Gomes , Ana Paula; Andersson , Frédéric; Ménigot , Sébastien; Batailler , Martine; Adriaensen , Hans; Migaud , Martine; Chaillou , Elodie

    2015-01-01

    National audience; Mass Spectrometry Imaging (MSI) provides easily high spatially resolved masses allowing characterization of endogenous lipids. These latter constitute about 70% of the composition of the white matter of the brain which can be implicated in developmental and/or cognitive troubles. In order to examine the molecular distribution of lipids in whole sheep brain, and especially in white/grey matter, we combined in vivo and ex vivo images, obtained in the same animals, using Magne...

  4. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    International Nuclear Information System (INIS)

    Biegon, A.; Kim, S.-W.; Logan, J.; Hooker, J.M.; Muench, L.; Fowler, J.S.

    2010-01-01

    Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. We report the first in vivo primate study to determine whether there is a direct effect of nicotine administration on brain aromatase. Brain aromatase availability was examined with positron emission tomography and the selective aromatase inhibitor ( 11 C)vorozole in six baboons before and after exposure to IV nicotine at .015 and .03 mg/kg. Nicotine administration produced significant, dose-dependent reductions in ( 11 C)vorozole binding. The amygdala and preoptic area showed the largest reductions. Plasma levels of nicotine and its major metabolite cotinine were similar to those found in cigarette smokers. Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior.

  5. Long-term occupational stress is associated with regional reductions in brain tissue volumes.

    Directory of Open Access Journals (Sweden)

    Eva Blix

    Full Text Available There are increasing reports of cognitive and psychological declines related to occupational stress in subjects without psychiatric premorbidity or major life trauma. The underlying neurobiology is unknown, and many question the notion that the described disabilities represent a medical condition. Using PET we recently found that persons suffering from chronic occupational stress had limbic reductions in the 5-HT1A receptor binding potential. Here we examine whether chronic work-related stress is also associated with changes in brain structure. We performed MRI-based voxel-based morphometry and structural volumetry in stressed subjects and unstressed controls focusing on gray (GM and white matter (WM volumes, and the volumes of hippocampus, caudate, and putamen - structures known to be susceptible to neurotoxic changes. Stressed subjects exhibited significant reductions in the GM volumes of the anterior cingulate cortex and the dorsolateral prefrontal cortex. Furthermore, their caudate and putamen volumes were reduced, and the volumes correlated inversely to the degree of perceived stress. Our results add to previous data on chronic psychosocial stress, and indicate a morphological involvement of the frontostriatal circuits. The present findings of morphological changes in these regions confirm our previous conclusion that symptoms from occupational stress merit careful investigations and targeted treatment.

  6. Long-Term Occupational Stress Is Associated with Regional Reductions in Brain Tissue Volumes

    Science.gov (United States)

    Blix, Eva; Perski, Aleksander; Berglund, Hans; Savic, Ivanka

    2013-01-01

    There are increasing reports of cognitive and psychological declines related to occupational stress in subjects without psychiatric premorbidity or major life trauma. The underlying neurobiology is unknown, and many question the notion that the described disabilities represent a medical condition. Using PET we recently found that persons suffering from chronic occupational stress had limbic reductions in the 5-HT1A receptor binding potential. Here we examine whether chronic work-related stress is also associated with changes in brain structure. We performed MRI-based voxel-based morphometry and structural volumetry in stressed subjects and unstressed controls focusing on gray (GM) and white matter (WM) volumes, and the volumes of hippocampus, caudate, and putamen – structures known to be susceptible to neurotoxic changes. Stressed subjects exhibited significant reductions in the GM volumes of the anterior cingulate cortex and the dorsolateral prefrontal cortex. Furthermore, their caudate and putamen volumes were reduced, and the volumes correlated inversely to the degree of perceived stress. Our results add to previous data on chronic psychosocial stress, and indicate a morphological involvement of the frontostriatal circuits. The present findings of morphological changes in these regions confirm our previous conclusion that symptoms from occupational stress merit careful investigations and targeted treatment. PMID:23776438

  7. Interdisciplinary Residential Treatment of Posttraumatic Stress Disorder and Traumatic Brain Injury: Effects on Symptom Severity and Occupational Performance and Satisfaction

    Science.gov (United States)

    Speicher, Sarah M.; Walter, Kristen H.

    2014-01-01

    OBJECTIVE. This study examined outcomes of an 8-wk residential treatment program for veterans with posttraumatic stress disorder (PTSD) and a history of traumatic brain injury (TBI). METHOD. Twenty-six veterans completed the Canadian Occupational Performance Measure, Clinician-Administered PTSD Scale, Beck Depression Inventory–2nd Edition, and PTSD Checklist before and after treatment. RESULTS. Veterans demonstrated significant improvements in occupational performance and satisfaction with their performance, as well as in PTSD and depression symptom severity after residential PTSD/TBI treatment. Additionally, improvements in occupational performance and satisfaction were associated with decreases in depression symptom severity. CONCLUSION. Although preliminary, results suggest that veterans with PTSD and a history of TBI experienced significant decreases in PTSD and depression symptom severity and improvement in self-perception of performance and satisfaction in problematic occupational areas. Changes in occupational areas and depression symptom severity were related, highlighting the importance of interdisciplinary treatment. PMID:25005504

  8. Effects of dopaminergic drug treatments on in vivo radioligand binding to brain vesicular monoamine transporters

    Energy Technology Data Exchange (ETDEWEB)

    Kilbourn, Michael R; Frey, Kirk A; Vander Borght, Thierry; Sherman, Phillip S

    1996-05-01

    The effects of various dopaminergic drug treatments on the in vivo regional brain distribution of high-affinity radioligands ([{sup 11}C]dihydrotetrabenazine and [{sup 11}C]methoxytetrabenazine) for the rat brain vesicular monoamine transporter (VMAT2) were determined. Acute treatments with reserpine (2 mg/kg i.p.), tetrabenazine (10 mg/kg i.v.) or related benzoisoquinolines significantly reduced radiotracer binding in vivo. In contrast, radiotracer distributions remained unchanged after treatments with other dopaminergic drugs, whether given by single injection (haloperidol, 1 mg/kg i.p., pargyline 80 mg/kg), repeatedly (pargyline, 80 mg/kg s.c., 14 days), or by continuous infusion (deprenyl, 10 mg/kg/day, 5 days; L-DOPA methyl ester 100 mg/kg/day, 5 days). Repeated injections of tetrabenazine (5 mg/kg i.p., twice daily, 3 days) did not alter in vivo radioligand binding measured after allowing drug washout from the brain. These studies support the proposal that in vivo PET imaging of VMAT2 radioligands in patients with extrapyramidal movement disorders will not be affected by concurrent use of L-DOPA or deprenyl.

  9. Rat brain sagittal organotypic slice cultures as an ex vivo dopamine cell loss system.

    Science.gov (United States)

    McCaughey-Chapman, Amy; Connor, Bronwen

    2017-02-01

    Organotypic brain slice cultures are a useful tool to study neurological function as they provide a more complex, 3-dimensional system than standard 2-dimensional in vitro cell cultures. Building on a previously developed mouse brain slice culture protocol, we have developed a rat sagittal brain slice culture system as an ex vivo model of dopamine cell loss. We show that rat brain organotypic slice cultures remain viable for up to 6 weeks in culture. Using Fluoro-Gold axonal tracing, we demonstrate that the slice 3-dimensional cytoarchitecture is maintained over a 4 week culturing period, with particular focus on the nigrostriatal pathway. Treatment of the cultures with 6-hydroxydopamine and desipramine induces a progressive loss of Fluoro-Gold-positive nigral cells with a sustained loss of tyrosine hydroxylase-positive nigral cells. This recapitulates the pattern of dopaminergic degeneration observed in the rat partial 6-hydroxydopamine lesion model and, most importantly, the progressive pathology of Parkinson's disease. Our slice culture platform provides an advance over other systems, as we demonstrate for the first time 3-dimensional cytoarchitecture maintenance of rat nigrostriatal sagittal slices for up to 6 weeks. Our ex vivo organotypic slice culture system provides a long term cellular platform to model Parkinson's disease, allowing for the elucidation of mechanisms involved in dopaminergic neuron degeneration and the capability to study cellular integration and plasticity ex vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Exercise induces the release of heat shock protein 72 from the human brain in vivo

    OpenAIRE

    Lancaster, G. I.; Møller, K.; Nielsen, B.; Secher, N. H.; Febbraio, M. A.; Nybo, L.

    2004-01-01

    The present study tested the hypothesis that in response to physical stress the human brain has the capacity to release heat shock protein 72 (Hsp72) in vivo. Therefore, 6 humans (males) cycled for 180 minutes at 60% of their maximal oxygen uptake, and the cerebral Hsp72 response was determined on the basis of the internal jugular venous to arterial difference and global cerebral blood flow. At rest, there was a net balance of Hsp72 across the brain, but after 180 minutes of exercise, we were...

  11. SPECT and PET Serve as Molecular Imaging Techniques and in Vivo Biomarkers for Brain Metastases

    Directory of Open Access Journals (Sweden)

    Barbara Palumbo

    2014-06-01

    Full Text Available Nuclear medicine techniques (single photon emission computerized tomography, SPECT, and positron emission tomography, PET represent molecular imaging tools, able to provide in vivo biomarkers of different diseases. To investigate brain tumours and metastases many different radiopharmaceuticals imaged by SPECT and PET can be used. In this review the main and most promising radiopharmaceuticals available to detect brain metastases are reported. Furthermore the diagnostic contribution of the combination of SPECT and PET data with radiological findings (magnetic resonance imaging, MRI is discussed.

  12. In vivo imaging of brain androgen receptors in rats: a [18F]FDHT PET study

    International Nuclear Information System (INIS)

    Khayum, M.A.; Doorduin, J.; Antunes, I.F.; Kwizera, C.; Zijlma, R.; Boer, J.A. den; Dierckx, R.A.J.O.; Vries, E.F.J. de

    2015-01-01

    Introduction: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16β-[ 18 F]fluoro-5α-dihydrotestosterone ([ 18 F]FDHT) to image AR expression in the brain. Methods: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [ 18 F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1 mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution. Results: PET imaging and ex vivo biodistribution studies showed low [ 18 F]FDHT uptake in all brain regions, except pituitary. [ 18 F]FDHT uptake in the surrounding cranial bones was high and increased over time. [ 18 F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [ 18 F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone. Conclusion: The results of this study indicate that imaging of AR availability in rat brain with [ 18 F]FDHT PET is not feasible. The low AR expression in the brain, the

  13. Multifunctional nanoparticle platforms for in vivo MRI enhancement and photodynamic therapy of a rat brain cancer

    Science.gov (United States)

    Kopelman, Raoul; Lee Koo, Yong-Eun; Philbert, Martin; Moffat, Bradford A.; Ramachandra Reddy, G.; McConville, Patrick; Hall, Daniel E.; Chenevert, Thomas L.; Bhojani, Mahaveer Swaroop; Buck, Sarah M.; Rehemtulla, Alnawaz; Ross, Brian D.

    2005-05-01

    A paradigm for brain cancer detection, treatment, and monitoring is established. Multifunctional biomedical nanoparticles (30-60 nm) containing photosensitizer externally deliver reactive oxygen species (ROS) to cancer cells while simultaneously enhancing magnetic resonance imaging (MRI) contrast providing real-time tumor kill measurement. Plasma residence time control and specific cell targeting are achieved. A 5 min treatment in rats halted and even reversed in vivo tumor growth after 3-4 days post-treatment.

  14. Multifunctional nanoparticle platforms for in vivo MRI enhancement and photodynamic therapy of a rat brain cancer

    International Nuclear Information System (INIS)

    Kopelman, Raoul; Lee Koo, Yong-Eun; Philbert, Martin; Moffat, Bradford A.; Ramachandra Reddy, G.; McConville, Patrick; Hall, Daniel E.; Chenevert, Thomas L.; Bhojani, Mahaveer Swaroop; Buck, Sarah M.; Rehemtulla, Alnawaz; Ross, Brian D.

    2005-01-01

    A paradigm for brain cancer detection, treatment, and monitoring is established. Multifunctional biomedical nanoparticles (30-60 nm) containing photosensitizer externally deliver reactive oxygen species (ROS) to cancer cells while simultaneously enhancing magnetic resonance imaging (MRI) contrast providing real-time tumor kill measurement. Plasma residence time control and specific cell targeting are achieved. A 5 min treatment in rats halted and even reversed in vivo tumor growth after 3-4 days post-treatment

  15. Multifunctional nanoparticle platforms for in vivo MRI enhancement and photodynamic therapy of a rat brain cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kopelman, Raoul [Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor MI 48109 (United States)]. E-mail: kopelman@umich.edu; Lee Koo, Yong-Eun [Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor MI 48109 (United States); Philbert, Martin [Environmental Health Sciences, niversity of Michigan (United States); Moffat, Bradford A. [Department of Radiology, The University of Michigan (United States); Ramachandra Reddy, G. [Molecular Therapeutics, Inc., Ann Arbor, MI 48104 (United States); McConville, Patrick [Molecular Therapeutics, Inc., Ann Arbor, MI 48104 (United States); Hall, Daniel E. [Department of Radiology, University of Michigan (United States); Chenevert, Thomas L. [Department of Radiology, University of Michigan (United States); Bhojani, Mahaveer Swaroop [Department of Radiation Oncology, University of Michigan (United States); Buck, Sarah M. [Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor MI 48109 (United States); Rehemtulla, Alnawaz [Department of Radiation Oncology, University of Michigan (United States); Ross, Brian D. [Department of Radiology, University of Michigan (United States)

    2005-05-15

    A paradigm for brain cancer detection, treatment, and monitoring is established. Multifunctional biomedical nanoparticles (30-60 nm) containing photosensitizer externally deliver reactive oxygen species (ROS) to cancer cells while simultaneously enhancing magnetic resonance imaging (MRI) contrast providing real-time tumor kill measurement. Plasma residence time control and specific cell targeting are achieved. A 5 min treatment in rats halted and even reversed in vivo tumor growth after 3-4 days post-treatment.

  16. In vivo electron paramagnetic resonance oximetry and applications in the brain

    Directory of Open Access Journals (Sweden)

    John M Weaver

    2017-01-01

    Full Text Available Molecular oxygen (O2 is essential to brain function and mechanisms necessary to regulate variations in delivery or utilization of O2 are crucial to support normal brain homeostasis, physiology and energy metabolism. Any imbalance in cerebral tissue partial pressure of O2 (pO2 levels may lead to pathophysiological complications including increased reactive O2 species generation leading to oxidative stress when tissue O2 level is too high or too low. Accordingly, the need for oximetry methods, which assess cerebral pO2 in vivo and in real time, is imperative to understand the role of O2 in various metabolic and disease states, including the effects of treatment and therapy options. In this review, we provide a brief overview of the common in vivo oximetry methodologies for measuring cerebral pO2 . We discuss the advantages and limitations of oximetry methodologies to measure cerebral pO2 in vivo followed by a more in-depth review of electron paramagnetic resonance oximetry spectroscopy and imaging using several examples of current electron paramagnetic resonance oximetry applications in the brain.

  17. Robust methods to create ex vivo minimum deformation atlases for brain mapping.

    Science.gov (United States)

    Janke, Andrew L; Ullmann, Jeremy F P

    2015-02-01

    Highly detailed ex vivo 3D atlases of average structure are of critical importance to neuroscience and its current push to understanding the global microstructure of the brain. Multiple single slice histology sections can no longer provide sufficient detail of inter-slice microstructure and lack out of plane resolution. Two ex vivo methods have emerged that can create such detailed models. High-field micro MRI with the addition of contrast media has allowed intact whole brain microstructure imaging with an isotropic resolution of 15 μm in mouse. Blockface imaging has similarly evolved to a point where it is now possible to image an entire brain in a rigorous fashion with an out of plane resolution of 10 μm. Despite the destruction of the tissue as part of this process it allows a reconstructed model that is free from cutting artifacts. Both of these methods have been utilised to create minimum deformation atlases that are representative of the respective populations. The MDA atlases allow us unprecedented insight into the commonality and differences in microstructure in cortical structures in specific taxa. In this paper we provide an overview of how to create such MDA models from ex vivo data. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. In vivo imaging of brain ischemia using an oxygen-dependent degradative fusion protein probe.

    Directory of Open Access Journals (Sweden)

    Youshi Fujita

    Full Text Available Within the ischemic penumbra, blood flow is sufficiently reduced that it results in hypoxia severe enough to arrest physiological function. Nevertheless, it has been shown that cells present within this region can be rescued and resuscitated by restoring perfusion and through other protective therapies. Thus, the early detection of the ischemic penumbra can be exploited to improve outcomes after focal ischemia. Hypoxia-inducible factor (HIF-1 is a transcription factor induced by a reduction in molecular oxygen levels. Although the role of HIF-1 in the ischemic penumbra remains unknown, there is a strong correlation between areas with HIF-1 activity and the ischemic penumbra. We recently developed a near-infrared fluorescently labeled-fusion protein, POH-N, with an oxygen-dependent degradation property identical to the alpha subunit of HIF-1. Here, we conduct in vivo imaging of HIF-active regions using POH-N in ischemic brains after transient focal cerebral ischemia induced using the intraluminal middle cerebral artery occlusion technique in mice. The results demonstrate that POH-N enables the in vivo monitoring and ex vivo detection of HIF-1-active regions after ischemic brain injury and suggest its potential in imaging and drug delivery to HIF-1-active areas in ischemic brains.

  19. A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion.

    Science.gov (United States)

    Shelton, Laura M; Mukherjee, Purna; Huysentruyt, Leanne C; Urits, Ivan; Rosenberg, Joshua A; Seyfried, Thomas N

    2010-09-01

    Glioblastoma multiforme (GBM) is a rapidly progressive disease of morbidity and mortality and is the most common form of primary brain cancer in adults. Lack of appropriate in vivo models has been a major roadblock to developing effective therapies for GBM. A new highly invasive in vivo GBM model is described that was derived from a spontaneous brain tumor (VM-M3) in the VM mouse strain. Highly invasive tumor cells could be identified histologically on the hemisphere contralateral to the hemisphere implanted with tumor cells or tissue. Tumor cells were highly expressive for the chemokine receptor CXCR4 and the proliferation marker Ki-67 and could be identified invading through the pia mater, the vascular system, the ventricular system, around neurons, and over white matter tracts including the corpus callosum. In addition, the brain tumor cells were labeled with the firefly luciferase gene, allowing for non-invasive detection and quantitation through bioluminescent imaging. The VM-M3 tumor has a short incubation time with mortality occurring in 100% of the animals within approximately 15 days. The VM-M3 brain tumor model therefore can be used in a pre-clinical setting for the rapid evaluation of novel anti-invasive therapies.

  20. Dynamic Remodeling of Pericytes In Vivo Maintains Capillary Coverage in the Adult Mouse Brain

    Directory of Open Access Journals (Sweden)

    Andrée-Anne Berthiaume

    2018-01-01

    Full Text Available Summary: Direct contact and communication between pericytes and endothelial cells is critical for maintenance of cerebrovascular stability and blood-brain barrier function. Capillary pericytes have thin processes that reach hundreds of micrometers along the capillary bed. The processes of adjacent pericytes come in close proximity but do not overlap, yielding a cellular chain with discrete territories occupied by individual pericytes. Little is known about whether this pericyte chain is structurally dynamic in the adult brain. Using in vivo two-photon imaging in adult mouse cortex, we show that while pericyte somata were immobile, the tips of their processes underwent extensions and/or retractions over days. The selective ablation of single pericytes provoked exuberant extension of processes from neighboring pericytes to contact uncovered regions of the endothelium. Uncovered capillary regions had normal barrier function but were dilated until pericyte contact was regained. Pericyte structural plasticity may be critical for cerebrovascular health and warrants detailed investigation. : Pericyte-endothelial contact is important for many aspects of cerebrovascular health. Berthiaume et al. use longitudinal two-photon imaging to show that the processes of brain capillary pericytes are structurally plastic in vivo. Their processes can grow hundreds of micrometers to ensure contact with exposed endothelium following ablation of a single pericyte. Keywords: capillary, pericyte, endothelium, blood-brain barrier, blood flow, plasticity, two-photon imaging, Alzheimer’s disease, dementia, stroke

  1. In vivo synthesis of phosphatidylcholine in rat brain via the phospholipid methylation pathway

    Science.gov (United States)

    Lakher, Michael; Wurtman, Richard J.

    1987-01-01

    The in vivo synthesis of brain phosphatidylcholine (PC) by the methylation of phosphatidylethanolamine (PE) was examined. (H-3)methyl)methionine was infused i.c.v., by indwelling cannula, and brain samples were taken 0.5-18 h thereafter and assayed for (H-3)PC, as well as for its biosynthetic intermediates (H-3)phosphatidyl monomethylethanolamine ((H-3)PMME) and (H-3)phosphatidyl dimethylethanolamine ((H-3)PDME), and for (H-3)lysophosphatidylcholine ((H-3)LPC) and S-(H-3)adenosylmethionine ((H-3)SAM). Most of the (H-3)PC (79-94 percent) was present ipsilateral to the infusion site; indicating that the radioactivity in the (H-3)PC was primarily of intracerebral origin, and not taken up from the blood. Moreover, only very low levels of (H-3)PC were attained in brains of animals receiving (H-3)methionine i.p. and these levels were symmetrically distributed. (H-3)PMME and (H-3)PDME turned over with apparent half-lives of 2.2 h and 2.4 h. In contrast, the accumulation of brain (H-3)PC was biphasic, suggesting the existence of two pools, the more labile of which turned over rapidly (t(sub 1/2) = 5 h) and was formed for as long as (H-3)PMME and (H-3)PDME are present in the brain, and another, which was distinguishable only at 18 h after the (H-3)methionine infusion. (The latter pool may have been synthesized from (H-3)choline that was released via the hydrolysis of some of the brain (H-3)PC previously formed by the methylation of PE.) Subcellular fractionation of brain tissue obtained after in vivo labelling with (H-3)methionine revealed that mitochondrial PC had the highest specific radioactivity (dpm per micromol total lipid phosphorus), and myelin the least. These observations affirm that rat brain does synthesize PC in vivo by methylating PE, and the technique provides an experimental system which may be useful for examining the physiological regulation of this process.

  2. Novel flurbiprofen derivatives with improved brain delivery: synthesis, in vitro and in vivo evaluations.

    Science.gov (United States)

    Zheng, Dan; Shuai, Xiao; Li, Yanping; Zhou, Peng; Gong, Tao; Sun, Xun; Zhang, Zhirong

    2016-09-01

    Tarenflurbil (R-flurbiprofen) was acknowledged as a promising candidate in Alzheimer's disease (AD) therapy. However, the Phase III study of tarenflurbil was extremely restricted by its poor delivery efficiency to the brain. To tackle this problem, the novel carriers for tarenflurbil, racemic flurbiprofen (FLU) derivatives (FLU-D1 and FLU-D2) modified by N,N-dimethylethanolamine-related structures were synthesized and characterized. These derivatives showed good safety level in vitro and they possessed much higher cellular uptake efficiency in brain endothelial cells than FLU did. More importantly, the uptake experiments suggested that they were internalized via active transport mechanisms. Biodistribution studies in rats also illustrated a remarkably enhanced accumulation of these derivatives in the brain. FLU-D2, the ester linkage form of these derivatives, achieved a higher brain-targeting efficiency. Its C max and AUC 0- t were enhanced by 12.09-fold and 4.61-fold, respectively compared with those of FLU. Additionally, it could be hydrolyzed by esterase in the brain to release the parent FLU, which might facilitate its therapeutic effect. These in vitro and in vivo results highlighted the improvement of the brain-targeted delivery of FLU by making use of N,N-dimethylethanolamine ligand, with which an active transport mechanism was involved.

  3. Radiotracers for the in vivo PET imagine of acetylcholinesterase in the brain

    International Nuclear Information System (INIS)

    Kilbourn, M.R.; Snyder, S.E.; Nguyen, T.; Koeppe, R.A.; Frey, K.A.; Kuhl, D.E.

    1997-01-01

    Regional brain pharmacokinetics of the piperidinyl esters have been determined in the primate brain, using Positron Emission Tomographic (PET) imaging. The propionate ester shows a faster and more complete rate of hydrolysis in regions of AChE, such as the striatum and the cortex. Regional hydrolysis rates (combined forward rate constants, k3) for these radiotracers can be calculated using a simplified analysis of tissue-time activity curves, without a need for determining metabolite-corrected plasma levels. In the striatum of the monkey, the propionate ester shows a reaction rate with the enzyme that is almost two-fold faster than the isobutyrate ester. These radiolabeled esters form a new approach to the measurement of in vivo function of AChE in the mammalian brain, including humans, and provide a method to assess changes in such enzyme activity as a result of disease or pharmacological intervention

  4. Radiotracers for the in vivo PET imagine of acetylcholinesterase in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Kilbourn, M.R.; Snyder, S.E.; Nguyen, T.; Koeppe, R.A.; Frey, K.A.; Kuhl, D.E. [University of Michigan Medical School, An Arbor (United States). Division of Nuclear Medicine

    1997-10-01

    Regional brain pharmacokinetics of the piperidinyl esters have been determined in the primate brain, using Positron Emission Tomographic (PET) imaging. The propionate ester shows a faster and more complete rate of hydrolysis in regions of AChE, such as the striatum and the cortex. Regional hydrolysis rates (combined forward rate constants, k3) for these radiotracers can be calculated using a simplified analysis of tissue-time activity curves, without a need for determining metabolite-corrected plasma levels. In the striatum of the monkey, the propionate ester shows a reaction rate with the enzyme that is almost two-fold faster than the isobutyrate ester. These radiolabeled esters form a new approach to the measurement of in vivo function of AChE in the mammalian brain, including humans, and provide a method to assess changes in such enzyme activity as a result of disease or pharmacological intervention 10 refs., 5 figs.

  5. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System.

    Science.gov (United States)

    Beliveau, Vincent; Ganz, Melanie; Feng, Ling; Ozenne, Brice; Højgaard, Liselotte; Fisher, Patrick M; Svarer, Claus; Greve, Douglas N; Knudsen, Gitte M

    2017-01-04

    The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT 1A , 5-HT 1B , 5-HT 2A , and 5-HT 4 ) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system of the human brain. We present a high-resolution positron emission tomography (PET)- and magnetic resonance imaging-based human brain atlas of important serotonin receptors and the transporter. The regional PET-derived binding measures correlate strongly with the corresponding autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into a protein density map of the serotonin (5-hydroxytryptamine, 5-HT) system. Next, we compared the regional receptor/transporter protein densities with mRNA levels and uncovered unique associations between protein expression and density at high detail. This new in vivo neuroimaging atlas of the 5-HT system not only provides insight in the human brain's regional protein

  6. Occupational, Physical, and Speech Therapy Treatment Activities During Inpatient Rehabilitation for Traumatic Brain Injury.

    Science.gov (United States)

    Beaulieu, Cynthia L; Dijkers, Marcel P; Barrett, Ryan S; Horn, Susan D; Giuffrida, Clare G; Timpson, Misti L; Carroll, Deborah M; Smout, Randy J; Hammond, Flora M

    2015-08-01

    To describe the use of occupational therapy (OT), physical therapy (PT), and speech therapy (ST) treatment activities throughout the acute rehabilitation stay of patients with traumatic brain injury. Multisite prospective observational cohort study. Inpatient rehabilitation settings. Patients (N=2130) admitted for initial acute rehabilitation after traumatic brain injury. Patients were categorized on the basis of admission FIM cognitive scores, resulting in 5 fairly homogeneous cognitive groups. Not applicable. Percentage of patients engaged in specific activities and mean time patients engaged in these activities for each 10-hour block of time for OT, PT, and ST combined. Therapy activities in OT, PT, and ST across all 5 cognitive groups had a primary focus on basic activities. Although advanced activities occurred in each discipline and within each cognitive group, these advanced activities occurred with fewer patients and usually only toward the end of the rehabilitation stay. The pattern of activities engaged in was both similar to and different from patterns seen in previous practice-based evidence studies with different rehabilitation diagnostic groups. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  7. In vivo evidence of methamphetamine induced attenuation of brain tissue oxygenation as measured by EPR oximetry

    Science.gov (United States)

    Weaver, John; Yang, Yirong; Purvis, Rebecca; Weatherwax, Theodore; Rosen, Gerald M.; Liu, Ke Jian

    2014-01-01

    Abuse of methamphetamine (METH) is a major and significant societal problem in the US, as a number of studies have suggested that METH is associated with increased cerebrovascular events, hemorrhage or vasospasm. Although cellular and molecular mechanisms involved in METH-induced toxicity are not completely understood, changes in brain O2 may play an important role and contribute to METH-induced neurotoxicity including dopaminergic receptor degradation. Given that O2 is the terminal electron acceptor for many enzymes that are important in brain function, the impact of METH on brain tissue pO2 in vivo remains largely uncharacterized. This study investigated striatal tissue pO2 changes in male C57BL/6 mice (16–20g) following METH administration using EPR oximetry, a highly sensitive modality to measure pO2 in vivo, in situ and in real time. We demonstrate that 20 min after a single injection of METH (8 mg/kg i.v.), the striatal pO2 was reduced to 81% of the pretreatment level and exposure to METH for 3 consecutive days further attenuated striatal pO2 to 64%. More importantly, pO2 did not recover fully to control levels even 24 hrs after administration of a single dose of METH. and continual exposure to METH exacerbates the condition. We also show a reduction in cerebral blood flow associated with a decreased brain pO2 indicating an ischemic condition. Our findings suggests that administration of METH can attenuate brain tissue pO2, which may lead to hypoxic insult, thus a risk factor for METH-induced brain injury and the development of stroke in young adults. PMID:24412707

  8. In vivo real-time multiphoton imaging of T lymphocytes in the mouse brain after experimental stroke

    DEFF Research Database (Denmark)

    Fumagalli, Stefano; Coles, Jonathan A; Ejlerskov, Patrick

    2011-01-01

    To gain a better understanding of T cell behavior after stroke, we have developed real-time in vivo brain imaging of T cells by multiphoton microscopy after middle cerebral artery occlusion.......To gain a better understanding of T cell behavior after stroke, we have developed real-time in vivo brain imaging of T cells by multiphoton microscopy after middle cerebral artery occlusion....

  9. Degradation of dynorphin A in brain tissue in vivo and in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Young, E.A.; Walker, J.M.; Houghten, R.; Akil, H.

    1987-07-01

    The demonstration of analgesia following in vivo administration of dynorphin A (Dyn A) has been difficult. In contrast, a number of electrophysiological and behavioral effects reported with in vivo injection of Dyn A can be produced by des-tyrosine dynorphin A (Dyn A 2-17). This suggested the extremely rapid amino terminal degradation of dynorphin A. To test this hypothesis, we examined the degradation of dynorphin A following in vivo injection into the periaqueductal gray (PAG) as well as in vitro using rat brain membranes under receptor binding conditions. In vivo, we observed the rapid amino terminal cleavage of tyrosine to yield the relatively more stable destyrosine dynorphin A. This same cleavage after tyrosine was observed in vitro. Inhibition of this aminopeptidase activity in vitro was observed by the addition of dynorphin A 2-17 or dynorphin A 7-17 but not after the addition of dynorphin A 1-13, dynorphin A 1-8, dynorphin B or alpha-neo-endorphin suggesting a specific enzyme may be responsible. The detection of the behaviorally active des-tyrosine dynorphin A following in vivo injection of dynorphin A suggests that this peptide may play an important physiological role.

  10. Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Andreas Üllen

    Full Text Available Peripheral leukocytes can exacerbate brain damage by release of cytotoxic mediators that disrupt blood-brain barrier (BBB function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl formed via the myeloperoxidase (MPO-H2O2-Cl(- system. In the present study we examined the role of leukocyte activation, leukocyte-derived MPO and MPO-generated oxidants on BBB function in vitro and in vivo. In a mouse model of lipopolysaccharide (LPS-induced systemic inflammation, neutrophils that had become adherent released MPO into the cerebrovasculature. In vivo, LPS-induced BBB dysfunction was significantly lower in MPO-deficient mice as compared to wild-type littermates. Both, fMLP-activated leukocytes and the MPO-H2O2-Cl(- system inflicted barrier dysfunction of primary brain microvascular endothelial cells (BMVEC that was partially rescued with the MPO inhibitor 4-aminobenzoic acid hydrazide. BMVEC treatment with the MPO-H2O2-Cl(- system or activated neutrophils resulted in the formation of plasmalogen-derived chlorinated fatty aldehydes. 2-chlorohexadecanal (2-ClHDA severely compromised BMVEC barrier function and induced morphological alterations in tight and adherens junctions. In situ perfusion of rat brain with 2-ClHDA increased BBB permeability in vivo. 2-ClHDA potently activated the MAPK cascade at physiological concentrations. An ERK1/2 and JNK antagonist (PD098059 and SP600125, respectively protected against 2-ClHDA-induced barrier dysfunction in vitro. The current data provide evidence that interference with the MPO pathway could protect against BBB dysfunction under (neuroinflammatory conditions.

  11. In vivo evidence of methamphetamine induced attenuation of brain tissue oxygenation as measured by EPR oximetry

    International Nuclear Information System (INIS)

    Weaver, John; Yang, Yirong; Purvis, Rebecca; Weatherwax, Theodore; Rosen, Gerald M.; Liu, Ke Jian

    2014-01-01

    Abuse of methamphetamine (METH) is a major and significant societal problem in the US, as a number of studies have suggested that METH is associated with increased cerebrovascular events, hemorrhage or vasospasm. Although cellular and molecular mechanisms involved in METH-induced toxicity are not completely understood, changes in brain O 2 may play an important role and contribute to METH-induced neurotoxicity including dopaminergic receptor degradation. Given that O 2 is the terminal electron acceptor for many enzymes that are important in brain function, the impact of METH on brain tissue pO 2 in vivo remains largely uncharacterized. This study investigated striatal tissue pO 2 changes in male C57BL/6 mice (16–20 g) following METH administration using EPR oximetry, a highly sensitive modality to measure pO 2 in vivo, in situ and in real time. We demonstrate that 20 min after a single injection of METH (8 mg/kg i.v.), the striatal pO 2 was reduced to 81% of the pretreatment level and exposure to METH for 3 consecutive days further attenuated striatal pO 2 to 64%. More importantly, pO 2 did not recover fully to control levels even 24 h after administration of a single dose of METH and continual exposure to METH exacerbates the condition. We also show a reduction in cerebral blood flow associated with a decreased brain pO 2 indicating an ischemic condition. Our findings suggests that administration of METH can attenuate brain tissue pO 2 , which may lead to hypoxic insult, thus a risk factor for METH-induced brain injury and the development of stroke in young adults. - Highlights: • Explored striatal tissue pO 2 in vivo after METH administration by EPR oximetry. • pO 2 was reduced by 81% after a single dose and 64% after 3 consecutive daily doses. • pO 2 did not recover fully to control levels even 24 h after a single dose. • Decrease in brain tissue pO 2 may be associated with a decrease in CBF. • Administration of methamphetamine may lead to hypoxic

  12. In vivo evidence of methamphetamine induced attenuation of brain tissue oxygenation as measured by EPR oximetry

    Energy Technology Data Exchange (ETDEWEB)

    Weaver, John, E-mail: jmweaver@salud.unm.edu [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Yang, Yirong [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Purvis, Rebecca [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Weatherwax, Theodore [Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Rosen, Gerald M. [Center for Biomedical Engineering and Technology, University of Maryland, Baltimore, MD 21201 (United States); Center for EPR Imaging In Vivo Physiology, University of Maryland, Baltimore, MD 21201 (United States); Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States); Liu, Ke Jian [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States)

    2014-03-01

    Abuse of methamphetamine (METH) is a major and significant societal problem in the US, as a number of studies have suggested that METH is associated with increased cerebrovascular events, hemorrhage or vasospasm. Although cellular and molecular mechanisms involved in METH-induced toxicity are not completely understood, changes in brain O{sub 2} may play an important role and contribute to METH-induced neurotoxicity including dopaminergic receptor degradation. Given that O{sub 2} is the terminal electron acceptor for many enzymes that are important in brain function, the impact of METH on brain tissue pO{sub 2}in vivo remains largely uncharacterized. This study investigated striatal tissue pO{sub 2} changes in male C57BL/6 mice (16–20 g) following METH administration using EPR oximetry, a highly sensitive modality to measure pO{sub 2}in vivo, in situ and in real time. We demonstrate that 20 min after a single injection of METH (8 mg/kg i.v.), the striatal pO{sub 2} was reduced to 81% of the pretreatment level and exposure to METH for 3 consecutive days further attenuated striatal pO{sub 2} to 64%. More importantly, pO{sub 2} did not recover fully to control levels even 24 h after administration of a single dose of METH and continual exposure to METH exacerbates the condition. We also show a reduction in cerebral blood flow associated with a decreased brain pO{sub 2} indicating an ischemic condition. Our findings suggests that administration of METH can attenuate brain tissue pO{sub 2}, which may lead to hypoxic insult, thus a risk factor for METH-induced brain injury and the development of stroke in young adults. - Highlights: • Explored striatal tissue pO{sub 2}in vivo after METH administration by EPR oximetry. • pO{sub 2} was reduced by 81% after a single dose and 64% after 3 consecutive daily doses. • pO{sub 2} did not recover fully to control levels even 24 h after a single dose. • Decrease in brain tissue pO{sub 2} may be associated with a decrease in

  13. In Vivo MRI Mapping of Brain Iron Deposition across the Adult Lifespan.

    Science.gov (United States)

    Acosta-Cabronero, Julio; Betts, Matthew J; Cardenas-Blanco, Arturo; Yang, Shan; Nestor, Peter J

    2016-01-13

    Disruption of iron homeostasis as a consequence of aging is thought to cause iron levels to increase, potentially promoting oxidative cellular damage. Therefore, understanding how this process evolves through the lifespan could offer insights into both the aging process and the development of aging-related neurodegenerative brain diseases. This work aimed to map, in vivo for the first time with an unbiased whole-brain approach, age-related iron changes using quantitative susceptibility mapping (QSM)--a new postprocessed MRI contrast mechanism. To this end, a full QSM standardization routine was devised and a cohort of N = 116 healthy adults (20-79 years of age) was studied. The whole-brain and ROI analyses confirmed that the propensity of brain cells to accumulate excessive iron as a function of aging largely depends on their exact anatomical location. Whereas only patchy signs of iron scavenging were observed in white matter, strong, bilateral, and confluent QSM-age associations were identified in several deep-brain nuclei--chiefly the striatum and midbrain-and across motor, premotor, posterior insular, superior prefrontal, and cerebellar cortices. The validity of QSM as a suitable in vivo imaging technique with which to monitor iron dysregulation in the human brain was demonstrated by confirming age-related increases in several subcortical nuclei that are known to accumulate iron with age. The study indicated that, in addition to these structures, there is a predilection for iron accumulation in the frontal lobes, which when combined with the subcortical findings, suggests that iron accumulation with age predominantly affects brain regions concerned with motor/output functions. This study used a whole--brain imaging approach known as quantitative susceptibility mapping (QSM) to provide a novel insight into iron accumulation in the brain across the adult lifespan. Validity of the method was demonstrated by showing concordance with ROI analysis and prior knowledge

  14. Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat.

    Science.gov (United States)

    Wong, Yin Cheong; Ilkova, Trayana; van Wijk, Rob C; Hartman, Robin; de Lange, Elizabeth C M

    2018-01-01

    Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC-MS based approach. Rats (n=24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61μmol/kg, i.e. 0.56mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n=7) to measure the free drug concentration in the extracellular fluid of the striatum and cerebellum. Raclopride concentrations in all samples were analyzed by LC-MS. A population PK-RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics. In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10-h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO 30%). For the first time a predictive model that could describe

  15. A non-contact time-domain scanning brain imaging system: first in-vivo results

    Science.gov (United States)

    Mazurenka, M.; Di Sieno, L.; Boso, G.; Contini, D.; Pifferi, A.; Dalla Mora, A.; Tosi, A.; Wabnitz, H.; Macdonald, R.

    2013-06-01

    We present results of first in-vivo tests of an optical non-contact scanning imaging system, intended to study oxidative metabolism related processes in biological tissue by means of time-resolved near-infrared spectroscopy. Our method is a novel realization of the short source-detector separation approach and based on a fast-gated single-photon avalanche diode to detect late photons only. The scanning system is built in quasi-confocal configuration and utilizes polarizationsensitive detection. It scans an area of 4×4 cm2, recording images with 32×32 pixels, thus creating a high density of source-detector pairs. To test the system we performed a range of in vivo measurements of hemodynamic changes in several types of biological tissues, i.e. skin (Valsalva maneuver), muscle (venous and arterial occlusions) and brain (motor and cognitive tasks). Task-related changes in hemoglobin concentrations were clearly detected in skin and muscle. The brain activation shows weaker, but yet detectable changes. These changes were localized in pixels near the motor cortex area (C3). However, it was found that even very short hair substantially impairs the measurement. Thus the applicability of the scanner is limited to hairless parts of body. The results of our first in-vivo tests prove the feasibility of non-contact scanning imaging as a first step towards development of a prototype for biological tissue imaging for various medical applications.

  16. Transcranial vibro-acoustography can detect traumatic brain injury, in-vivo: Preliminary studies.

    Science.gov (United States)

    Suarez, Martin W; Dever, David D; Gu, Xiaohan; Ray Illian, P; McClintic, Abbi M; Mehic, Edin; Mourad, Pierre D

    2015-08-01

    Vibro-acoustography (VA) uses two or more beams of confocal ultrasound to generate local vibrations within their target tissue through induction of a time-dependent radiation force whose frequency equals that of the difference of the applied frequencies. While VA has proven effective for assaying the mechanical properties of clinically relevant tissue such as breast lesions and tissue calcifications, its application to brain remains unexplored. Here we investigate the ability of VA to detect acute and focal traumatic brain injury (TBI) in-vivo through the use of transcranially delivered high-frequency (2 MHz) diagnostic focused ultrasound to rat brain capable of generating measurable low-frequency (200-270 kHz) acoustic emissions from outside of the brain. We applied VA to acute sham-control and TBI model rats (sham N=6; TBI N=6) and observed that acoustic emissions, captured away from the site of TBI, had lower amplitudes for TBI as compared to sham-TBI animals. The sensitivity of VA to acute brain damage at frequencies currently transmittable across human skulls, as demonstrated in this preliminary study, supports the possibility that the VA methodology may one day serve as a technique for detecting TBI. Copyright © 2015. Published by Elsevier B.V.

  17. Simplified methods for in vivo measurement of acetylcholinesterase activity in rodent brain

    International Nuclear Information System (INIS)

    Kilbourn, Michael R.; Sherman, Phillip S.; Snyder, Scott E.

    1999-01-01

    Simplified methods for in vivo studies of acetylcholinesterase (AChE) activity in rodent brain were evaluated using N-[ 11 C]methylpiperidinyl propionate ([ 11 C]PMP) as an enzyme substrate. Regional mouse brain distributions were determined at 1 min (representing initial brain uptake) and 30 min (representing trapped product) after intravenous [ 11 C]PMP administration. Single time point tissue concentrations (percent injected dose/gram at 30 min), tissue concentration ratios (striatum/cerebellum and striatum/cortex ratios at 30 min), and regional tissue retention fractions (defined as percent injected dose 30 min/percent injected dose 1 min) were evaluated as measures of AChE enzymatic activity in mouse brain. Studies were carried out in control animals and after dosing with phenserine, a selective centrally active AChE inhibitor; neostigmine, a peripheral cholinesterase inhibitor; and a combination of the two drugs. In control and phenserine-treated animals, absolute tissue concentrations and regional retention fractions provide good measures of dose-dependent inhibition of brain AChE; tissue concentration ratios, however, provide erroneous conclusions. Peripheral inhibition of cholinesterases, which changes the blood pharmacokinetics of the radiotracer, diminishes the sensitivity of all measures to detect changes in central inhibition of the enzyme. We conclude that certain simple measures of AChE hydrolysis rates for [ 11 C]PMP are suitable for studies where alterations of the peripheral blood metabolism of the tracer are kept to a minimum

  18. Simplified methods for in vivo measurement of acetylcholinesterase activity in rodent brain

    Energy Technology Data Exchange (ETDEWEB)

    Kilbourn, Michael R. E-mail: mkilbour@umich.edu; Sherman, Phillip S.; Snyder, Scott E

    1999-07-01

    Simplified methods for in vivo studies of acetylcholinesterase (AChE) activity in rodent brain were evaluated using N-[{sup 11}C]methylpiperidinyl propionate ([{sup 11}C]PMP) as an enzyme substrate. Regional mouse brain distributions were determined at 1 min (representing initial brain uptake) and 30 min (representing trapped product) after intravenous [{sup 11}C]PMP administration. Single time point tissue concentrations (percent injected dose/gram at 30 min), tissue concentration ratios (striatum/cerebellum and striatum/cortex ratios at 30 min), and regional tissue retention fractions (defined as percent injected dose 30 min/percent injected dose 1 min) were evaluated as measures of AChE enzymatic activity in mouse brain. Studies were carried out in control animals and after dosing with phenserine, a selective centrally active AChE inhibitor; neostigmine, a peripheral cholinesterase inhibitor; and a combination of the two drugs. In control and phenserine-treated animals, absolute tissue concentrations and regional retention fractions provide good measures of dose-dependent inhibition of brain AChE; tissue concentration ratios, however, provide erroneous conclusions. Peripheral inhibition of cholinesterases, which changes the blood pharmacokinetics of the radiotracer, diminishes the sensitivity of all measures to detect changes in central inhibition of the enzyme. We conclude that certain simple measures of AChE hydrolysis rates for [{sup 11}C]PMP are suitable for studies where alterations of the peripheral blood metabolism of the tracer are kept to a minimum.

  19. Simultaneous in vivo recording of local brain temperature and electrophysiological signals with a novel neural probe

    Science.gov (United States)

    Fekete, Z.; Csernai, M.; Kocsis, K.; Horváth, Á. C.; Pongrácz, A.; Barthó, P.

    2017-06-01

    Objective. Temperature is an important factor for neural function both in normal and pathological states, nevertheless, simultaneous monitoring of local brain temperature and neuronal activity has not yet been undertaken. Approach. In our work, we propose an implantable, calibrated multimodal biosensor that facilitates the complex investigation of thermal changes in both cortical and deep brain regions, which records multiunit activity of neuronal populations in mice. The fabricated neural probe contains four electrical recording sites and a platinum temperature sensor filament integrated on the same probe shaft within a distance of 30 µm from the closest recording site. The feasibility of the simultaneous functionality is presented in in vivo studies. The probe was tested in the thalamus of anesthetized mice while manipulating the core temperature of the animals. Main results. We obtained multiunit and local field recordings along with measurement of local brain temperature with accuracy of 0.14 °C. Brain temperature generally followed core body temperature, but also showed superimposed fluctuations corresponding to epochs of increased local neural activity. With the application of higher currents, we increased the local temperature by several degrees without observable tissue damage between 34-39 °C. Significance. The proposed multifunctional tool is envisioned to broaden our knowledge on the role of the thermal modulation of neuronal activity in both cortical and deeper brain regions.

  20. In vivo rat deep brain imaging using photoacoustic computed tomography (Conference Presentation)

    Science.gov (United States)

    Lin, Li; Li, Lei; Zhu, Liren; Hu, Peng; Wang, Lihong V.

    2017-03-01

    The brain has been likened to a great stretch of unknown territory consisting of a number of unexplored continents. Small animal brain imaging plays an important role charting that territory. By using 1064 nm illumination from the side, we imaged the full coronal depth of rat brains in vivo. The experiment was performed using a real-time full-ring-array photoacoustic computed tomography (PACT) imaging system, which achieved an imaging depth of 11 mm and a 100 μm radial resolution. Because of the fast imaging speed of the full-ring-array PACT system, no animal motion artifact was induced. The frame rate of the system was limited by the laser repetition rate (50 Hz). In addition to anatomical imaging of the blood vessels in the brain, we continuously monitored correlations between the two brain hemispheres in one of the coronal planes. The resting states in the coronal plane were measured before and after stroke ligation surgery at a neck artery.

  1. In vivo 1H spectroscopy of the human brain at 1.5 tesla. Preliminary experience at a clinical installation

    DEFF Research Database (Denmark)

    Henriksen, O; Larsson, H; Jensen, K M

    1990-01-01

    In vivo localized water suppressed proton spectroscopy of human brain was carried out on 15 healthy volunteers and 2 patients suffering from a brain tumour and an infarction, respectively. The measurements were performed on a whole body MR system, operating at 1.5 tesla using the stimulated echo...

  2. Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

    Directory of Open Access Journals (Sweden)

    Salem HF

    2015-07-01

    Full Text Available Heba F Salem,1 Sayed M Ahmed,2 Ashraf E Hassaballah,3 Mahmoud M Omar1,4 1Department of Pharmaceutics and Industrial Pharmacy, Beni-suef University, 2Department of Industrial Pharmacy, Assiut University, 3Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assuit, 4Department of Pharmaceutics and Industrial Pharmacy, Deraya University, Egypt Background: The blood–brain barrier prevents many drug moieties from reaching the central nervous system. Therefore, glutathione-modulated nanoliposomes have been engineered to enhance the targeting of flucytosine to the brain. Methods: Glutathione-modulated nanoliposomes were prepared by thin-film hydration technique and evaluated in the primary brain cells of rats. Lecithin, cholesterol, and span 65 were mixed at 1:1:1 molar ratio. The molar percentage of PEGylated glutathione varied from 0 mol% to 0.75 mol%. The cellular binding and the uptake of the targeted liposomes were both monitored by epifluorescent microscope and flow cytometry techniques. A biodistribution and a pharmacokinetic study of flucytosine and flucytosine-loaded glutathione–modulated liposomes was carried out to evaluate the in vivo brain-targeting efficiency. Results: The size of glutathione-modulated nanoliposomes was <100 nm and the zeta potential was more than -65 mV. The cumulative release reached 70% for certain formulations. The cellular uptake increased as molar percent of glutathione increased to reach the maximum at 0.75 mol%. The uptake of the targeted liposomes by brain cells of the rats was three times greater than that of the nontargeted liposomes. An in vivo study showed that the relative efficiency was 2.632±0.089 and the concentration efficiency was 1.590±0.049, and also, the drug-targeting index was 3.670±0.824. Conclusion: Overall, these results revealed that glutathione-PEGylated nanoliposomes enhance the effective delivery of flucytosine to brain and could become a promising new

  3. Electrosteric stealth Rivastigmine loaded liposomes for brain targeting: preparation, characterization, ex vivo, bio-distribution and in vivo pharmacokinetic studies.

    Science.gov (United States)

    Nageeb El-Helaly, Sara; Abd Elbary, Ahmed; Kassem, Mohamed A; El-Nabarawi, Mohamed A

    2017-11-01

    Being one of the highly effective drugs in treatment of Alzheimer's disease, Rivastigmine brain targeting is highly demandable, therefore liposomal dispersion of Rivastigmine was prepared containing 2 mol% PEG-DSPE added to Lecithin, Didecyldimethyl ammonium bromide (DDAB), Tween 80 in 1:0.02:0.25 molar ratio. A major challenge during the preparation of liposomes is maintaining a stable formulation, therefore the aim of our study was to increase liposomal stability by addition of DDAB to give an electrostatic stability and PEG-DSPE to increase stability by steric hindrance, yielding what we called an electrosteric stealth (ESS) liposomes. A medium nano-sized liposome (478 ± 4.94 nm) with a nearly neutral zeta potential (ZP, -8 ± 0.2 mV) and an entrapment efficiency percentage of 48 ± 6.22 was prepared. Stability studies showed no major alteration after three months storage period concerning particle size, polydispersity index, ZP, entrapment efficiency and in vitro release study confirming the successful formation of a stable liposomes. No histopathological alteration was recorded for ESS liposomes of the sheep nasal mucosa. While ESS liposomes showed higher % of drug permeating through the sheep nasal mucosa (48.6%) than the drug solution (28.7%). On completing the in vivo pharmacokinetic studies of 36 rabbits showed 424.2% relative bioavailability of the mean plasma levels of the formula ESS compared to that of RHT intranasal solution and 486% relative bioavailability of the mean brain levels.

  4. Protein synthesis in the rat brain: a comparative in vivo and in vitro study in immature and adult animals

    International Nuclear Information System (INIS)

    Shahbazian, F.M.

    1985-01-01

    Rates of protein synthesis of CNS and other organs were compared in immature and adult rats by in vivo and slice techniques with administration of flooding doses of labeled precursor. The relationship between synthesis and brain region, cell type, subcellular fraction, or MW was examined. Incorporation of [ 14 C]valine into protein of CNS regions in vivo was about 1.2% per hour for immature rats and 0.6% for adults. For slices, the rates decreased significantly more in adults. In adult organs, the highest synthesis rate in vivo was found in liver (2.2% per hour) followed by kidney, spleen, lung, heart, brain, and muscle (0.5% per hour). In immature animals synthesis was highest in liver and spleen (2.5% per hour) and lowest in muscle (0.9% per hour). Slices all showed lower rates than in vivo, especially in adults. In vivo, protein synthesis rates of immature neurons and astrocytes and adult neurons exceeded those of whole brain, while that in adult astrocytes was the same. These results demonstrate a developmental difference of protein synthesis (about double in immature animals) in all brain cells, cell fractions and most brain protein. Similarly the decreased synthesis in brain slices - especially in adults, affects most proteins and structural elements

  5. In vivo study about specific captation of 125 I-insulin by rat brain structures

    International Nuclear Information System (INIS)

    Sanvitto, G.L.

    1986-01-01

    The specific captation of 125 I-insulin was evaluated by brain structures, as olfactory bulbous, hypothalamus and cerebellum in rats, from in vivo experiences that including two different aspects: captation measure of 125 I-insulin after the intravenous injection of the labelled hormone, in fed rats and in rats with 48 h of fast or convulsion, procedure by the pentylene tetrazole; captation measure of 125 I-insulin after intra-cerebral-ventricular injection of the labelled hormone in fed rats. (C.G.C.)

  6. Brain physiological state evaluated by real-time multiparametric tissue spectroscopy in vivo

    Science.gov (United States)

    Mayevsky, Avraham; Barbiro-Michaely, Efrat; Kutai-Asis, Hofit; Deutsch, Assaf; Jaronkin, Alex

    2004-07-01

    The significance of normal mitochondrial function in cellular energy homeostasis as well as its involvement in acute and chronic neurodegenerative disease was reviewed recently (Nicholls & Budd. Physiol Rev. 80: 315-360, 2000). Nevertheless, monitoring of mitochondrial function in vivo and real time mode was not used by many investigators and is very rare in clinical practice. The main principle tool available for the evaluation of mitochondrial function is the monitoring of NADH fluorescence. In order to interpret correctly the changes in NADH redox state in vivo, it is necessary to correlate this signal to other parameters, reflecting O2 supply to the brain. Therefore, we have developed and applied a multiparametric optical monitoring system, by which microcirculatory blood flow and hemoglobin oxygenation is measured, together with mitochondrial NADH fluorescence. Since the calibration of these signals is not in absolute units, the simultaneous monitoring provide a practical tool for the interpretation of brain functional state under various pathophysiological conditions. The monitoring system combines a time-sharing fluorometer-reflectometer for the measurement of NADH fluorescence and hemoglobin oxygenation as well as a laser Doppler flowmeter for the recording of microcirculatory blood flow. A combined fiber optic probe was located on the surface of the brain using a skull cemented cannula. Rats and gerbils were exposed to anoxia, ischemia and spreading depression and the functional state of the brain was evaluated. The results showed a clear correlation between O2 supply/demand as well as, energy balance under the various pathophysiological conditions. This monitoring approach could be adapted to clinical monitoring of tissue vitality.

  7. Differences between in vitro and in vivo degradation of LHRH by rat brain and other organs

    International Nuclear Information System (INIS)

    Carone, F.A.; Stetler-Stevenson, M.A.; May, V.; LaBarbera, A.; Flouret, G.

    1987-01-01

    Homogenates of brain, pituitary, liver, lung, ovary, and testes were incubated with [ 1 -3,4- 3 H] luteinizing hormone-releasing hormone ([ 3 H]LHRH), and the profiles of metabolites generated as a function of time were determined. After 5 min of incubation, 5 was the predominant metabolite in most homogenates. Although the profiles of metabolites varied at different times intervals, metabolites 2, 3, 4, and 5, and in some instances 7 and 9, appeared to form simultaneously and were detectable at 10 min. Neither metabolite 6 nor other larger metabolites formed initially as dominant degradation products. The findings suggest cleavage of LHRH by the simultaneous action of several endopeptidases. After a single vascular transit of [ 3 H]LHRH, metabolites were determined in the venous blood of liver, lung, and brain of rats in vivo. There were no metabolites of [ 3 H]LHRH in venous blood liver and lung; however, metabolites 2-4 present in venous blood of the brain. Incubation of rat anterior pituitary cells with [ 3 H]LHRH yielded metabolites 1-4 but not metabolites 5 or 9 as in homogenates. Incubation of [ 3 H]LHRH with porcine follicular granulosa cells resulted in the generation of metabolites 2-7 and 9, similar to the profile in homogenates. Thus, since homogenates contain enzymes of disrupted cells, they do not always reflect mechanisms for in vivo hydrolysis of circulating LHRH. Brain degraded 12.1% of LHRH during a single vascular transit and may account for substantial degradation of the circulating hormone

  8. Differences between in vitro and in vivo degradation of LHRH by rat brain and other organs

    Energy Technology Data Exchange (ETDEWEB)

    Carone, F.A.; Stetler-Stevenson, M.A.; May, V.; LaBarbera, A.; Flouret, G.

    1987-09-01

    Homogenates of brain, pituitary, liver, lung, ovary, and testes were incubated with (brain of rats in vivo. There were no metabolites of (/sup 3/H)LHRH in venous blood liver and lung; however, metabolites 2-4 present in venous blood of the brain. Incubation of rat anterior pituitary cells with (/sup 3/H)LHRH yielded metabolites 1-4 but not metabolites 5 or 9 as in homogenates. Incubation of (/sup 3/H)LHRH with porcine follicular granulosa cells resulted in the generation of metabolites 2-7 and 9, similar to the profile in homogenates. Thus, since homogenates contain enzymes of disrupted cells, they do not always reflect mechanisms for in vivo hydrolysis of circulating LHRH. Brain degraded 12.1% of LHRH during a single vascular transit and may account for substantial degradation of the circulating hormone.

  9. Biographical disruption, adjustment and reconstruction of everyday occupations and work participation after mild traumatic brain injury. A focus group study.

    Science.gov (United States)

    Sveen, Unni; Søberg, Helene Lundgaard; Østensjø, Sigrid

    2016-11-01

    To explore traumatic brain injury (TBI) as a biographical disruption and to study the reconstruction of everyday occupations and work participation among individuals with mild TBI. Seven focus groups were conducted with 12 women and 8 men (22-60 years) who had sustained mild TBI and participated in a return-to-work program. Interviews were analyzed using qualitative content analysis. Four interrelated themes emerged: disruption of occupational capacity and balance; changes in self-perceptions; experience of time; and occupational adjustment and reconstruction. The meaning of the impairments lies in their impact on the individual's everyday occupations. The abandonment of meaningful daily occupations and the feeling of not recognizing oneself were experienced as threats to the sense of self. Successful integration of the past, present and future was paramount to continuing life activities. The unpredictability of the future seemed to permeate the entire process of adjustment and reconstruction of daily life. Our findings show that the concept of time is important in understanding and supporting the reconstruction of daily life after TBI. The fundamental work of rehabilitation is to ameliorate the disruptions caused by the injury, restoring a sense of personal narrative and supporting the ability to move forward with life. Implications for Rehabilitation Individuals with a protracted recovery after a mild traumatic brain injury must reconstruct a new way of being and acting in the world to achieve biographical continuity. The perceived anxiety regarding changes in self and occupational identity, as well as loss of control over the future, can be attenuated through informational sessions during the hospital stay and at follow-up visits. The significant personal costs of returning to full-time employment too early indicate the need for early and ongoing vocational support in achieving a successful return to work.

  10. Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo.

    Science.gov (United States)

    Malizia, A L; Melichar, J M; Brown, D J; Gunn, R N; Reynolds, A; Jones, T; Nutt, D J

    1997-01-01

    We describe the use of 11CRTI-55 and the Multiple Objects Coincidences Counter (MOCC) to detect in-vivo binding to peripheral serotonin reuptake sites (left chest comprising platelet and lung serotonin reuptake sites) in man. Displacement and preloading experiments with clomipramine and venlafaxine in two healthy volunteers demonstrated that 11CRTI-55 binding is decreased in a dose-dependent fashion by both these drugs which bind to the serotonin transporter. In addition parallel data from the total head curve (representing 11CRTI-55 binding to central serotonin and dopamine (DA) reuptake sites) suggest that prior blockade of the serotonin transporter may be a useful strategy to maximize radioactive counts in the head when measuring the DA transporter. The MOCC is likely to be useful to determine sequential indices of relative serotonin reuptake blockade in patients on treatment.

  11. Brain Transport Profiles of Ginsenoside Rb1 by Glucose Transporter 1: In Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Yu-Zhu Wang

    2018-04-01

    Full Text Available Ginsenoside Rb1 (Rb1 has been demonstrated its protection for central nervous system and is apparently highly distributed to the brain. The objective of this study was to characterize Rb1 transport at the blood–brain barrier (BBB using primary cultured rat brain microvascular endothelial cells (rBMEC, an in vitro BBB model. The initial uptake velocity of Rb1 in rBMEC was temperature- and concentration-dependent, and was significantly reduced by phloretin, an inhibitor of GLUT1 transporter, but was independent of metabolic inhibitor. Furthermore, the transport of Rb1 into rBMEC was significantly diminished in the presence of natural substrate α-D-glucose, suggesting a facilitated transport of Rb1 via GLUT1 transporter. The impact of GLUT1 on the distribution of Rb1 between brain and plasma was studied experimentally in rats. Administration of phloretin (5 mg/kg, i.v. to normal rats for consecutive 1 week before Rb1 (10 mg/kg, i.v. at 0.5, 2, and 6 h did not alter Rb1 concentrations in plasma, but resulted in significant decreased brain concentrations of Rb1 compared to in the phloretin-untreated normal rats (489.6 ± 58.3 versus 105.1 ± 15.1 ng/g, 193.8 ± 11.1 versus 84.8 ± 4.1 ng/g, and 114.2 ± 24.0 versus 39.9 ± 4.9 ng/g, respectively. The expression of GLUT1 in the phloretin-treated group by western blotting analysis in vitro and in vivo experiments was significantly decreased, indicating that the decreased transport of Rb1 in brain was well related to the down-regulated function and level of GLUT1. Therefore, our in vitro and in vivo results indicate that the transport of Rb1 at the BBB is at least partly mediated by GLUT1 transporter.

  12. Validation of In Vitro Cell-Based Human Blood-Brain Barrier Model Using Clinical Positron Emission Tomography Radioligands To Predict In Vivo Human Brain Penetration

    International Nuclear Information System (INIS)

    Mabondzo, A.; Guyot, A.C.; Bottlaender, M.; Deverre, J.R.; Tsaouin, K.; Balimane, P.V.

    2010-01-01

    We have evaluated a novel in vitro cell-based human blood-brain barrier (BBB) model that could predict in vivo human brain penetration for compounds with different BBB permeabilities using the clinical positron emission tomography (PET) data. Comparison studies were also performed to demonstrate that the in vitro cell-based human BBB model resulted in better predictivity over the traditional permeability model in discovery organizations, Caco-2 cells. We evaluated the in vivo BBB permeability of [ 18 F] and [ 11 C]-compounds in humans by PET imaging. The in vivo plasma-brain exchange parameters used for comparison were determined in humans by PET using a kinetic analysis of the radiotracer binding. For each radiotracer, the parameters were determined by fitting the brain kinetics of the radiotracer using a two-tissue compartment model of the ligand-receptor interaction. Bidirectional transport studies with the same compounds as in in vivo studies were carried out using the in vitro cell-based human BBB model as well as Caco-2 cells. The in vitro cell-based human BBB model has important features of the BBB in vivo and is suitable for discriminating between CNS and non-CNS marketed drugs. A very good correlation (r 2 =0.90; P≤0.001) was demonstrated between in vitro BBB permeability and in vivo permeability coefficient. In contrast, a poor correlation (r 2 = 0.17) was obtained between Caco-2 data and in vivo human brain penetration. This study highlights the potential of this in vitro cell-based human BBB model in drug discovery and shows that it can be an extremely effective screening tool for CNS programs. (authors)

  13. A high-resolution probabilistic in vivo atlas of human subcortical brain nuclei.

    Science.gov (United States)

    Pauli, Wolfgang M; Nili, Amanda N; Tyszka, J Michael

    2018-04-17

    Recent advances in magnetic resonance imaging methods, including data acquisition, pre-processing and analysis, have benefited research on the contributions of subcortical brain nuclei to human cognition and behavior. At the same time, these developments have led to an increasing need for a high-resolution probabilistic in vivo anatomical atlas of subcortical nuclei. In order to address this need, we constructed high spatial resolution, three-dimensional templates, using high-accuracy diffeomorphic registration of T 1 - and T 2 - weighted structural images from 168 typical adults between 22 and 35 years old. In these templates, many tissue boundaries are clearly visible, which would otherwise be impossible to delineate in data from individual studies. The resulting delineations of subcortical nuclei complement current histology-based atlases. We further created a companion library of software tools for atlas development, to offer an open and evolving resource for the creation of a crowd-sourced in vivo probabilistic anatomical atlas of the human brain.

  14. Anisotropic Conductivity Tensor Imaging of In Vivo Canine Brain Using DT-MREIT.

    Science.gov (United States)

    Jeong, Woo Chul; Sajib, Saurav Z K; Katoch, Nitish; Kim, Hyung Joong; Kwon, Oh In; Woo, Eung Je

    2017-01-01

    We present in vivo images of anisotropic electrical conductivity tensor distributions inside canine brains using diffusion tensor magnetic resonance electrical impedance tomography (DT-MREIT). The conductivity tensor is represented as a product of an ion mobility tensor and a scale factor of ion concentrations. Incorporating directional mobility information from water diffusion tensors, we developed a stable process to reconstruct anisotropic conductivity tensor images from measured magnetic flux density data using an MRI scanner. Devising a new image reconstruction algorithm, we reconstructed anisotropic conductivity tensor images of two canine brains with a pixel size of 1.25 mm. Though the reconstructed conductivity values matched well in general with those measured by using invasive probing methods, there were some discrepancies as well. The degree of white matter anisotropy was 2 to 4.5, which is smaller than previous findings of 5 to 10. The reconstructed conductivity value of the cerebrospinal fluid was about 1.3 S/m, which is smaller than previous measurements of about 1.8 S/m. Future studies of in vivo imaging experiments with disease models should follow this initial trial to validate clinical significance of DT-MREIT as a new diagnostic imaging modality. Applications in modeling and simulation studies of bioelectromagnetic phenomena including source imaging and electrical stimulation are also promising.

  15. Improved calibration technique for in vivo proton MRS thermometry for brain temperature measurement.

    Science.gov (United States)

    Zhu, M; Bashir, A; Ackerman, J J; Yablonskiy, D A

    2008-09-01

    The most common MR-based approach to noninvasively measure brain temperature relies on the linear relationship between the (1)H MR resonance frequency of tissue water and the tissue's temperature. Herein we provide the most accurate in vivo assessment existing thus far of such a relationship. It was derived by acquiring in vivo MR spectra from a rat brain using a high field (11.74 Tesla [T]) MRI scanner and a single-voxel MR spectroscopy technique based on a LASER pulse sequence. Data were analyzed using three different methods to estimate the (1)H resonance frequencies of water and the metabolites NAA, Cho, and Cr, which are used as temperature-independent internal (frequency) references. Standard modeling of frequency-domain data as composed of resonances characterized by Lorentzian line shapes gave the tightest resonance-frequency versus temperature correlation. An analysis of the uncertainty in temperature estimation has shown that the major limiting factor is an error in estimating the metabolite frequency. For example, for a metabolite resonance linewidth of 8 Hz, signal sampling rate of 2 Hz and SNR of 5, an accuracy of approximately 0.5 degrees C can be achieved at a magnetic field of 3T. For comparison, in the current study conducted at 11.74T, the temperature estimation error was approximately 0.1 degrees C.

  16. Long-term reproducibility of in vivo measures of specific binding of radioligands in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Kilbourn, Michael R. E-mail: mkilbour@umich.edu

    2004-07-01

    The long-term reproducibility of measures of in vivo specific binding of radiolabeled forms of (+)-{alpha}-dihydrotetrabenazine (DTBZ) and d-threo-methylphenidate (MPH) in rat brain was examined. All studies were done using a consistent bolus plus infusion protocol and calculation of equilibrium distribution volume ratios (DVR). Over a period of eight years striatal DVR values for DTBZ binding to the vesicular monoamine transporter 2 (VMAT2) in young adult (8-10 wks old) rats showed very good reproducibility (3.62{+-}0.33, N=35). Equivalent values were obtained using either tritiated or carbon-11 labeled DTBZ, and were irrespective of sex of animals. Older animals (78 wks old) showed losses (-45%) of specific binding. Striatal binding of MPH to the dopamine transporter (DAT) showed a similar reproducibility over a five year period (DVR=2.17{+-}0.39, N=52), again irrespective of radionuclide or sex. These studies demonstrate that use of a consistent in vivo technique can provide reliable measures of specific binding of radioligands to high affinity sites in the rat brain.

  17. In vivo field dependence of proton relaxation times in human brain, liver and skeletal muscle: a multicenter study

    DEFF Research Database (Denmark)

    Henriksen, O; de Certaines, J D; Spisni, A

    1993-01-01

    and MRS, the in vivo field dispersion of T1 and T2 has been measured in order to evaluate whether ex vivo data are representative for the in vivo situation. Brain, skeletal muscle, and liver of healthy human volunteers were studied. Fifteen MR units with a field strength ranging from 0.08 T to 1.5 T took......T1 and T2 relaxation times are fundamental parameters for signal contrast behaviour in MRI. A number of ex vivo relaxometry studies have dealt with the magnetic field dispersion of T1. By means of multicenter study within the frame of the COMAC BME Concerted Action on Tissue Characterization by MRI......, whereas no significant variations were seen for T2. Our in vivo data were generally in reasonable agreement with proposed models based on ex vivo measurements....

  18. Real-Time Amperometric Recording of Extracellular H2O2 in the Brain of Immunocompromised Mice: An In Vitro, Ex Vivo and In Vivo Characterisation Study

    Science.gov (United States)

    Reid, Caroline H.; Finnerty, Niall J.

    2017-01-01

    We detail an extensive characterisation study on a previously described dual amperometric H2O2 biosensor consisting of H2O2 detection (blank) and degradation (catalase) electrodes. In vitro investigations demonstrated excellent H2O2 sensitivity and selectivity against the interferent, ascorbic acid. Ex vivo studies were performed to mimic physiological conditions prior to in vivo deployment. Exposure to brain tissue homogenate identified reliable sensitivity and selectivity recordings up to seven days for both blank and catalase electrodes. Furthermore, there was no compromise in pre- and post-implanted catalase electrode sensitivity in ex vivo mouse brain. In vivo investigations performed in anaesthetised mice confirmed the ability of the H2O2 biosensor to detect increases in amperometric current following locally perfused/infused H2O2 and antioxidant inhibitors mercaptosuccinic acid and sodium azide. Subsequent recordings in freely moving mice identified negligible effects of control saline and sodium ascorbate interference injections on amperometric H2O2 current. Furthermore, the stability of the amperometric current was confirmed over a five-day period and analysis of 24-h signal recordings identified the absence of diurnal variations in amperometric current. Collectively, these findings confirm the biosensor current responds in vivo to increasing exogenous and endogenous H2O2 and tentatively supports measurement of H2O2 dynamics in freely moving NOD SCID mice. PMID:28698470

  19. Exploring sex differences in the adult zebra finch brain: In vivo diffusion tensor imaging and ex vivo super-resolution track density imaging.

    Science.gov (United States)

    Hamaide, Julie; De Groof, Geert; Van Steenkiste, Gwendolyn; Jeurissen, Ben; Van Audekerke, Johan; Naeyaert, Maarten; Van Ruijssevelt, Lisbeth; Cornil, Charlotte; Sijbers, Jan; Verhoye, Marleen; Van der Linden, Annemie

    2017-02-01

    Zebra finches are an excellent model to study the process of vocal learning, a complex socially-learned tool of communication that forms the basis of spoken human language. So far, structural investigation of the zebra finch brain has been performed ex vivo using invasive methods such as histology. These methods are highly specific, however, they strongly interfere with performing whole-brain analyses and exclude longitudinal studies aimed at establishing causal correlations between neuroplastic events and specific behavioral performances. Therefore, the aim of the current study was to implement an in vivo Diffusion Tensor Imaging (DTI) protocol sensitive enough to detect structural sex differences in the adult zebra finch brain. Voxel-wise comparison of male and female DTI parameter maps shows clear differences in several components of the song control system (i.e. Area X surroundings, the high vocal center (HVC) and the lateral magnocellular nucleus of the anterior nidopallium (LMAN)), which corroborate previous findings and are in line with the clear behavioral difference as only males sing. Furthermore, to obtain additional insights into the 3-dimensional organization of the zebra finch brain and clarify findings obtained by the in vivo study, ex vivo DTI data of the male and female brain were acquired as well, using a recently established super-resolution reconstruction (SRR) imaging strategy. Interestingly, the SRR-DTI approach led to a marked reduction in acquisition time without interfering with the (spatial and angular) resolution and SNR which enabled to acquire a data set characterized by a 78μm isotropic resolution including 90 diffusion gradient directions within 44h of scanning time. Based on the reconstructed SRR-DTI maps, whole brain probabilistic Track Density Imaging (TDI) was performed for the purpose of super resolved track density imaging, further pushing the resolution up to 40μm isotropic. The DTI and TDI maps realized atlas

  20. (+)- and (-)-N-allylnormetazocine binding sites in mouse brain: in vitro and in vivo characterization and regional distribution

    International Nuclear Information System (INIS)

    Compton, D.R.; Bagley, R.B.; Katzen, J.S.; Martin, B.R.

    1987-01-01

    In vivo and in vitro binding studies, both in whole brain and in selected areas, indicate that non-identical (+)- and (-)-NANM sites exist in the mouse brain, and each exhibits a different regional distribution. The in vivo binding of (+)- 3 H-NANM was found to be saturable at pharmacologically relevant doses, and represents a relatively small (10 - 22%) portion of total brain (+)- 3 H-NANM concentrations. The in vivo binding of (+)- 3 H-NANM was selectively displaced by (+)-NANM and PCP, and more sensitive to haloperidol and (+)-ketocyclazocine than the (-)- 3 H-NANM site. The in vivo binding of (-)- 3 H-NANM was selectively displaced by (-)-NANM, and more sensitive to naloxone and (-) ketocyclazocine than the (+)- 3 H-NANM site, and insensitive to PCP. This study indicates that the investigation of NANM binding sites is possible using in vivo binding techniques, and that each isomer apparently binds, in the mouse brain, to a single class of distinct sites. 32 references, 4 figures, 2 tables

  1. Study of brain uptake of etorphine, in vivo in the Baboon Papio-Papio, by positron emission tomography

    International Nuclear Information System (INIS)

    Artola, A.

    1983-01-01

    In order to study in vivo opiate receptors in brain, etorphine, a morphine-like drug was labelled with 11 C. Etorphine possesses an extremely high affinity for specific opiate binding sites. It passes easily through the blood-brain barrier. The brain pharmacokinetics of 11 C-etorphine was studied in vivo in the Baboon Papio-Papio, by positron emission tomography. 11 C-etorphine concentration reached its maximum two minutes after intravenous injection and then decreased rapidly. In some experiments, cyprenorphine, a morphine antagonist, was injected subsequently in order to study the displacement of the radioactive ligand from brain structures. Hepato-biliary and blood pharmacokinetics of 11 C-etorphine were also studied [fr

  2. Sigma1 and dopamine D2 receptor occupancy in the mouse brain after a single administration of haloperidol and two dopamine D2-like receptor ligands

    International Nuclear Information System (INIS)

    Ishiwata, Kiichi; Kawamura, Kazunori; Kobayashi, Tadayuki; Matsuno, Kiyoshi

    2003-01-01

    We investigated sigma 1 and dopamine D 2 receptor occupancy in mouse brain after a single injection of haloperidol, nemonapride, or spiperone using [ 11 C]SA4503 and [ 11 C]raclopride, respectively. Co-injection of the three compounds significantly blocked the uptake of each radioligand. Six hours later, only haloperidol blocked [ 11 C]SA4503 uptake, while all three reduced [ 11 C]raclopride uptake. Sigma 1 receptor occupancy by haloperidol was reduced to 19% at day 2 when D 2 receptor occupancy disappeared. [ 11 C]SA4503 would be applicable to the investigation of sigma 1 receptor occupancy of antispychotic drugs using PET

  3. The impact of group occupational therapy using a cueing system on executive function of preschool-aged children with brain lesions.

    Science.gov (United States)

    Seo, Sang-Min

    2018-02-01

    [Purpose] This study investigates the effects of group occupational therapy using a cueing system on the executive function of preschool-aged children with brain lesions. [Subjects and Methods] Six preschool-aged children with brain lesions participated in this study. A 24-session occupational therapy program (1 session/week, 50 minutes/session) designed based on a cueing system was administered to examine the changes in the participants' executive function. The behavior rating inventory of executive function-preschool (BRIEF-P) was used to check the magnitude of improvement of executive functions after therapy. [Results] A Wilcoxon signed rank test revealed that occupational therapy significantly improved all domains, indices, and the global executive composite in the BRIEF-P. [Conclusion] The occupational therapy intervention incorporating a type of cognitive behavioral approach known as the cueing system may assist improving executive functions in preschool-aged children with brain lesions.

  4. In vivo quantitation of metabolite concentrations in the brain by means of proton MRS

    DEFF Research Database (Denmark)

    Henriksen, O

    1995-01-01

    MRS offers unique possibilities for non-invasive studies of biochemistry in the human brain in vivo. A growing body of evidence suggests that proton MRS may contribute to the clinical evaluation of a number of pathologies including ischaemia, tumours, epilepsy, metabolic and neuropaediatric...... (kg wet weight)-1 range between 8.2 and 17.2 (mean 10.2), 5.9 and 11.6 (mean 7.2), 1.1 and 2.0 (mean 1.5) and 3.9 and 8.1 (mean 6.1), respectively. So far only a limited number of clinical studies has been published including studies of acute stroke, multiple sclerosis and Alzheimer's disease...

  5. In vivo measurement of water self diffusion in the human brain by magnetic resonance imaging

    DEFF Research Database (Denmark)

    Thomsen, C; Henriksen, O; Ring, P

    1987-01-01

    A new pulse sequence for in vivo diffusion measurements by magnetic resonance imaging (MRI) is introduced. The pulse sequence was tested on phantoms to evaluate the accuracy, reproducibility and inplane variations. The sensitivity of the sequence was tested by measuring the self diffusion...... coefficient of water with different temperatures. This phantom study showed that the water self diffusion could be measured accurately and that the inplane deviation was less than +/- 10 per cent. Seven healthy volunteers were studied with a 10 mm thick slice through the lateral ventricles, clear differences...... between grey and white matter as well as regional differences within the white matter were seen. In two patients with infarction, alternations in water self diffusion were seen in the region of the infarct. Likewise, pronounced changes in brain water self diffusion were observed in a patient with benign...

  6. A multiphoton laser scanning microscope setup for transcranial in vivo brain imaging on mice

    Science.gov (United States)

    Nase, Gabriele; Helm, P. Johannes; Reppen, Trond; Ottersen, Ole Petter

    2005-12-01

    We describe a multiphoton laser scanning microscope setup for transcranial in vivo brain imaging in mice. The modular system is based on a modified industrial standard Confocal Scanning Laser Microscope (CSLM) and is assembled mainly from commercially available components. A special multifunctional stage, which is optimized for both laser scanning microscopic observation and preparative animal surgery, has been developed and built. The detection unit includes a highly efficient photomultiplier tube installed in a Peltier-cooled thermal box shielding the detector from changes in room temperature and from distortions caused by external electromagnetic fields. The images are recorded using a 12-bit analog-to-digital converter. Depending on the characteristics of the staining, individual nerve cells can be imaged down to at least 100μm below the intact cranium and down to at least 200μm below the opened cranium.

  7. Design and in vivo evaluation of more efficient and selective deep brain stimulation electrodes

    Science.gov (United States)

    Howell, Bryan; Huynh, Brian; Grill, Warren M.

    2015-08-01

    Objective. Deep brain stimulation (DBS) is an effective treatment for movement disorders and a promising therapy for treating epilepsy and psychiatric disorders. Despite its clinical success, the efficiency and selectivity of DBS can be improved. Our objective was to design electrode geometries that increased the efficiency and selectivity of DBS. Approach. We coupled computational models of electrodes in brain tissue with cable models of axons of passage (AOPs), terminating axons (TAs), and local neurons (LNs); we used engineering optimization to design electrodes for stimulating these neural elements; and the model predictions were tested in vivo. Main results. Compared with the standard electrode used in the Medtronic Model 3387 and 3389 arrays, model-optimized electrodes consumed 45-84% less power. Similar gains in selectivity were evident with the optimized electrodes: 50% of parallel AOPs could be activated while reducing activation of perpendicular AOPs from 44 to 48% with the standard electrode to 0-14% with bipolar designs; 50% of perpendicular AOPs could be activated while reducing activation of parallel AOPs from 53 to 55% with the standard electrode to 1-5% with an array of cathodes; and, 50% of TAs could be activated while reducing activation of AOPs from 43 to 100% with the standard electrode to 2-15% with a distal anode. In vivo, both the geometry and polarity of the electrode had a profound impact on the efficiency and selectivity of stimulation. Significance. Model-based design is a powerful tool that can be used to improve the efficiency and selectivity of DBS electrodes.

  8. In vivo labeling of phencyclidine (PCP) receptors with 3H-TCP in the mouse brain

    International Nuclear Information System (INIS)

    Maurice, T.; Vignon, J.

    1990-01-01

    The phencyclidine (PCP) derivative N-[1-(2-thienyl)cyclohexyl]-piperidine (3H-TCP) was used to label in vivo the N-methyl-D-aspartate (NMDA) receptor-associated ionic channel in the mouse brain. After the injection of a tracer dose of 3H-TCP, a spread labeling throughout the brain was observed, but was the highest in the cerebellum. Preadministration of unlabeled TCP (30 mg/kg) resulted in a 90% reduction of 3H-TCP binding. PCP, TCP, MK-801, dexoxadrol, ketamine, and SKF 10,047 isomers dose-dependently prevented the in vivo 3H-TCP binding. ID50 determined in the cerebrum and the cerebellum were respectively correlated with K0.5 for 3H TCP high (rat cortex) and low affinity (rat cerebellum) sites in vitro. The pharmacological specificity of the 3H-TCP binding site in the cerebellum was significantly different from that in the cerebrum. ID50 values were generally higher than in the cerebrum and, particularly, MK-801, the most potent drug in the cerebrum, was without significant effect in the cerebellum, at any time and at doses as high as 30 mg/kg. N-[1-(2-benzo(b) thiophenyl)cyclohexyl]piperidine (BTCP), desipramine, and atropine showed a more efficient prevention of 3H-TCP binding in the cerebellum than in the cerebrum. The prevention of the binding by TCP or PCP, at doses close to their ID50 values, was rapid and then decreased slowly. The effect of MK-801 was long-lasting. This study confirm previous in vitro studies: 3H-TCP is an efficient tool for the labeling of the NMDA receptor-associated ionic channel

  9. Human in-vivo brain magnetic resonance current density imaging (MRCDI)

    DEFF Research Database (Denmark)

    Göksu, Cihan; Hanson, Lars G.; Siebner, Hartwig R

    2017-01-01

    is modulated by these shifts, allowing to determine ΔBz,c for the reconstruction of the current flow and ohmic conductivity. Here, we demonstrate reliable ΔBz,c measurements in-vivo in the human brain based on multi-echo spin echo (MESE) and steady-state free precession free induction decay (SSFP......-FID) sequences. In a series of experiments, we optimize their robustness for in-vivo measurements while maintaining a good sensitivity to the current-induced fields. We validate both methods by assessing the linearity of the measured ΔBz,c with respect to the current strength. For the more efficient SSFP...... of ΔBz,c fields as weak as 1 nT, caused by currents of 1 mA strength. Comparison of the ΔBz,c measurements with simulated ΔBz,c images based on FEM calculations and individualized head models reveals significant linear correlations in all subjects, but only for the stray field-corrected data. As final...

  10. Ultrasonic brain therapy: First trans-skull in vivo experiments on sheep using adaptive focusing

    Science.gov (United States)

    Pernot, Mathieu; Aubry, Jean-Francois; Tanter, Michael; Fink, Mathias; Boch, Anne-Laure; Kujas, Michèle

    2004-05-01

    A high-power prototype dedicated to trans-skull therapy has been tested in vivo on 20 sheep. The array is made of 200 high-power transducers working at 1-MHz central and is able to reach 260 bars at focus in water. An echographic array connected to a Philips HDI 1000 system has been inserted in the therapeutic array in order to perform real-time monitoring of the treatment. A complete craniotomy has been performed on half of the treated animal models in order to get a reference model. On the other animals, a minimally invasive surgery has been performed thanks to a time-reversal experiment: a hydrophone was inserted at the target inside the brain thanks to a 1-mm2 craniotomy. A time-reversal experiment was then conducted through the skull bone with the therapeutic array to treat the targeted point. For all the animals a specified region around the target was treated thanks to electronic beam steering. Animals were finally divided into three groups and sacrificed, respectively, 0, 1, and 2 weeks after treatment. Finally, histological examination confirmed tissue damage. These in vivo experiments highlight the strong potential of high-power time-reversal technology.

  11. Treatment of Experimental Brain Tumors with Trombospondin-1 Derived Peptides: an In Vivo Imaging Study

    Directory of Open Access Journals (Sweden)

    A. Bogdanov, Jr.

    1999-11-01

    Full Text Available Antiangiogenic and antiproliferative effects of synthetic D-reverse peptides derived from the type 1 repeats of thrombospondin (TSP1 [1,2] were studied in rodent C6 glioma and 9L gliosarcomas. To directly measure tumor size and vascular parameters, we employed in vivo magnetic resonance (MR imaging and corroborated results by traditional morphometric tissue analysis. Rats bearing either C6 or 9L tumors were treated with TSP1-derived peptide (D-reverse amKRFKQDGGWSHWSPWSSac, n=13 or a control peptide (D-reverse am KRAKQAGGASHASPASSac, n=12 at 10 mg/kg, administered either intravenously or through subcutaneous miniosmotic pumps starting 10 days after tumor implantation. Eleven days later, the effect of peptide treatment was evaluated. TSP1 peptide-treated 9L tumors (50.7±44.2 mm3, n=7 and C6 tumors (41.3±34.2 mm3, n=6 were significantly smaller than tumors treated with control peptide (9L: 215.7±67.8 mm3, n=6; C6:184.2±105.2 mm3, n=6. In contrast, the in vivo vascular volume fraction, the mean vascular area (determined by microscopy, and the microvascular density of tumors were not significantly different in any of the experimental groups. In cell culture, TSP1, and the amKRFKQDGGWSHWSPWSSac peptide showed antiproliferative effects against C6 with an IC of 45 nM for TSP1. These results indicate that TSP1derived peptides retard brain tumor growth presumably as a result of slower de novo blood vessel formation and synergistic direct antiproliferative effects on tumor cells. We also show that in vivo MR imaging can be used to assess treatment efficacy of novel antiangiogenic drugs non-invasively, which has obvious implications for clinical trials.

  12. Photothermal effect of infrared lasers on ex vivo lamb brain tissues

    Science.gov (United States)

    Özgürün, Baturay; Gülsoy, Murat

    2018-02-01

    Here, the most suitable infrared laser for a neurosurgery operation is suggested, among 1940-nm thulium fiber, 1470-nm diode, 1070-nm ytterbium fiber and 980-nm diode lasers. Cortical and subcortical ex-vivo lamb brain tissues are exposed to the laser light with the combinations of some laser parameters such as output power, energy density, operation mode (continuous and pulsed-modulated) and operation time. In this way, the greatest ablation efficiency associated with the best neurosurgical laser type can be defined. The research can be divided into two parts; pre-dosimetry and dosimetry studies. The former is used to determine safe operation zones for the dosimetry study by defining coagulation and carbonization onset times for each of the brain tissues. The latter is the main part of this research, and both tissues are exposed to laser irradiation with various energy density levels associated with the output power and operation time. In addition, photo-thermal effects are compared for two laser operation modes, and then coagulation and ablation diameters to calculate the ablation efficiency are measured under a light microscope. Consequently, results are compared graphically and statistically, and it is found that thulium and 1470-nm diode lasers can be utilized as subcortical and cortical tissue ablator devices, respectively.

  13. Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Gillings, Nic; Comley, Robert A

    2009-01-01

    The serotonin 4 receptor (5-HT(4) receptor) is known to be involved in learning and memory. We evaluated for the first time the quantification of a novel 5-HT(4) receptor radioligand, (11)C-SB207145, for in vivo brain imaging with PET in humans. METHODS: For evaluation of reproducibility, 6...

  14. The Effect of Occupation-based Cognitive Rehabilitation for Traumatic Brain Injury: A Meta-analysis of Randomized Controlled Trials.

    Science.gov (United States)

    Park, Hae Yean; Maitra, Kinsuk; Martinez, Kristina Marie

    2015-06-01

    Traumatic brain injury (TBI) is the leading cause of death and disability among people younger than 35 years in the United States. Cognitive difficulty is a common consequence of TBI. To address cognitive deficits of patients with TBI, various cognitive rehabilitation approaches have been used for the clinical setting. The purpose of this study was to investigate the overall effect of occupation-based cognitive rehabilitation on patients' improvement in cognitive performance components, activity of daily living (ADL) performance, and values, beliefs and spirituality functions of patients with TBI. The papers used in this study were retrieved from the Cochrane Database, EBSCO (CINAHL), PsycINFO, PubMed and Web of Science published between 1997 and 2014. The keywords for searching were cognitive, rehabilitation, occupation, memory, attention, problem-solving, executive function, ADL, values, beliefs, spirituality, randomized controlled trials and TBI. For the meta-analysis, we examined 60 effect sizes from nine studies that are related to the occupation-based cognitive rehabilitation on persons with TBI. In persons with TBI, overall mental functions, ADL, and values, beliefs and spirituality were significantly improved in the groups that received occupation-based cognitive rehabilitation compared with comparison groups (mean d = 0.19, p cognitive rehabilitation would be beneficial for individuals with TBI for improving daily functioning and positively be able to affect their psychosocial functions. Collecting many outcome measures in studies with relatively few participants and the final data are less reliable than the whole instrument itself. Future research should evaluate the effectiveness of specific occupation-based cognitive rehabilitations programmes in order to improve consistency among rehabilitation providers. Copyright © 2015 John Wiley & Sons, Ltd.

  15. Formulation and In-vivo Pharmacokinetic Consideration of Intranasal Microemulsion and Mucoadhesive Microemulsion of Rivastigmine for Brain Targeting.

    Science.gov (United States)

    Shah, Brijesh; Khunt, Dignesh; Misra, Manju; Padh, Harish

    2018-01-02

    Presence of tight junctions in blood brain barrier (BBB) pose a major hurdle for delivery of drug and severely affects adequate therapeutic concentration to reach the brain. In present work, we have selected Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, which exhibits extensive first-pass metabolism, resulting in limited absolute bioavailability (36%). RHT shows extremely low aqueous solubility and poor penetration, resulting in inadequate concentration reaching the brain, thus necessitating frequent oral dosing. To overcome these problems of RHT, microemulsion (ME) and mucoadhesive microemulsion (MME) of RHT were formulated for brain targeting via intranasal delivery route and compared on the basis of in vivo pharmacokinetics. ME and MME formulations containing RHT were developed by water titration method. Characterization of ME and MME was done for various physicochemical parameters, nasal spray pattern, and in vivo pharmacokinetics quantitatively and qualitatively (gamma scintigraphy studies). The developed ME and MME were transparent having globule size approximately in the range of 53-55 nm. Pharmacokinetic studies showed higher values for C max and DTP for intranasal RHT: CH-ME over RHT-ME, thus indicating the effect of chitosan in modulating tight junctions, thereby enhanced paracellular transport of RHT. Gamma scintigraphy and in vivo pharmacokinetic study suggested enhanced RHT concentration, upon intranasal administration of RHT:CH-ME, compare with other groups administered formulations intranasally. These findings suggested the potential of non-invasive intranasal route for brain delivery, especially for therapeutics, facing challenges in oral administration.

  16. Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein

    Science.gov (United States)

    Lee, Anna M; Miksys, Sharon; Tyndale, Rachel F

    2006-01-01

    CYP2B6 is a drug-metabolizing enzyme expressed in the liver and brain that can metabolize bupropion (Zyban®, a smoking cessation drug), activate tobacco-smoke nitrosamines, and inactivate nicotine. Hepatic CYP2B6 is induced by phenobarbital and induction may affect in vivo nicotine disposition, while brain CYP2B6 induction may affect local levels of centrally acting substrates. We investigated the effect of chronic phenobarbital treatment on induction of in vivo nicotine disposition and CYP2B6 expression in the liver and brain of African Green (Vervet) monkeys. Monkeys were split into two groups (n=6 each) and given oral saccharin daily for 22 days; one group was supplemented with 20 mg kg−1 phenobarbital. Monkeys were given a 0.1 mg kg−1 nicotine dose subcutaneously before and after treatment. Phenobarbital treatment resulted in a significant, 56%, decrease (P=0.04) in the maximum nicotine plasma concentration and a 46% decrease (P=0.003) in the area under the concentration–time curve. Phenobarbital also increased hepatic CYP2B6 protein expression. In monkey brain, significant induction (Pphenobarbital treatment in monkeys resulted in increased in vivo nicotine disposition, and induced hepatic and brain CYP2B6 protein levels and cellular expression. This induction may alter the metabolism of CYP2B6 substrates including peripherally acting drugs such as cyclophosphamide and centrally acting drugs such as bupropion, ecstasy and phencyclidine. PMID:16751792

  17. MRI-controlled interstitial ultrasound brain therapy: An initial in-vivo study

    Science.gov (United States)

    N'Djin, W. Apoutou; Burtnyk, Mathieu; Lipsman, Nir; Bronskill, Michael; Schwartz, Michael; Kucharczyk, Walter; Chopra, Rajiv

    2012-11-01

    The recent emergence at the clinical level of minimally-invasive focal therapy such as laser-induced thermal therapy (LITT) has demonstrated promise in the management of brain metastasis [1], although control over the spatial pattern of heating is limited. Delivery of HIFU from minimally-invasive applicators enables high spatial control of the heat deposition in biological tissues, large treatment volumes and high treatment rate in well chosen conditions [2,3]. In this study, the feasibility of MRI-guided interstitial ultrasound therapy in brain was studies in-vivo in a porcine model. A prototype system originally developed for transurethral ultrasound therapy [4,5,6] was used in this study. Two burr holes of 12 mm in diameter were created in the animal's skull to allow the insertion of the therapeutic ultrasound applicator (probe) into the brain at two locations (right and left frontal lobe). A 4-element linear ultrasound transducer (f = 8 MHz) was mounted at the tip of a 25-cm linear probe (6 mm in diameter). The target boundary was traced to cover in 2D a surface compatible with the treatment of a 2 cm brain tumor. Acoustic power of each element and rotation rate of the device were adjusted in real-time based on MR-thermometry feedback control to optimize heat deposition at the target boundary [2,4,5]. Two MRT-controlled ultrasound brain treatments per animal have been performed using a maximal surface acoustic power of 10W.cm-2. In all cases, it was possible to increase accurately the temperature of the brain tissues in the targeted region over the 55°C threshold necessary for the creation of irreversible thermal lesion. Tissue changes were visible on T1w contrast-enhanced images immediately after treatment. These changes were also evident on T2w FSE images taken 2 hours after the 1st treatment and correlated well with the temperature image. On average, the targeted volume was 4.7 ± 2.3 cm3 and the 55°C treated volume was 6.7 ± 4.4 cm3. The volumetric

  18. Intracellular Redox State Revealed by In Vivo 31P MRS Measurement of NAD+ and NADH Contents in Brains

    Science.gov (United States)

    Lu, Ming; Zhu, Xiao-Hong; Zhang, Yi; Chen, Wei

    2015-01-01

    Purpose Nicotinamide adenine dinucleotide (NAD), in oxidized (NAD+) or reduced (NADH) form, plays key roles in cellular metabolism. Intracellular NAD+/NADH ratio represents the cellular redox state; however, it is difficult to measure in vivo. We report here a novel in vivo 31P MRS method for noninvasive measurement of intracellular NAD concentrations and NAD+/NADH ratio in the brain. Methods It uses a theoretical model to describe the NAD spectral patterns at a given field for quantification. Standard NAD solutions and independent cat brain measurements at 9.4 T and 16.4 T were used to evaluate this method. We also measured T1 values of brain NAD. Results Model simulation and studies of solutions and brains indicate that the proposed method can quantify submillimolar NAD concentrations with reasonable accuracy if adequate 31P MRS signal-to-noise ratio and linewidth were obtained. The NAD concentrations and NAD+/NADH ratio of cat brains measured at 16.4 T and 9.4 T were consistent despite the significantly different T1 values and NAD spectra patterns at two fields. Conclusion This newly established 31P MRS method makes it possible for the first time to noninvasively study the intracellular redox state and its roles in brain functions and diseases, and it can potentially be applied to other organs. PMID:23843330

  19. In vivo 1H MR spectroscopic findings in traumatic contusion of ICR mouse brain induced by fluid percussion injury

    International Nuclear Information System (INIS)

    Choi, Chi-Bong; Kim, Hwi-Yool; Han, Duk-Young; Kang, Young-Woon; Han, Young-Min; Jeun, Sin-Soo; Choe, Bo-Young

    2005-01-01

    Purpose: The purpose of this study was to investigate the proton metabolic differences of the right parietal cortex with experimental brain contusions of ICR mouse induced by fluid percussion injury (FPI) compared to normal controls and to test the possibility that 1 H magnetic resonance spectroscopy (MRS) findings could provide neuropathologic criteria in the diagnosis and monitoring of traumatic brain contusions. Materials and methods: A homogeneous group of 20 ICR male mice was used for MRI and in vivo 1 H MRS. Using image-guided, water-suppressed in vivo 1 H MRS with a 4.7 T MRI/MRS system, we evaluated the MRS measurement of the relative proton metabolite ratio between experimental brain contusion of ICR mouse and healthy control subjects. Results: After trauma, NAA/Cr ratio, as a neuronal marker decreased significantly versus controls, indicating neuronal loss. The ratio of NAA/Cr in traumatic brain contusions was 0.90 ± 0.11, while that in normal control subjects was 1.13 ± 0.12 (P = 0.001). The Cho/Cr ratio had a tendency to rise in experimental brain contusions (P = 0.02). The Cho/Cr ratio was 0.91 ± 0.17, while that of the normal control subjects was 0.76 ± 0.15. However, no significant difference of Glx/Cr was established between the experimental traumatic brain injury models and the normal controls. Discussion and conclusions: The present 1 H MRS study shows significant proton metabolic changes of parietal cortex with experimental brain contusions of ICR mouse induced by FPI compared to normal controls. In vivo 1 H MRS may be a useful modality for the clinical evaluation of traumatic contusions and could aid in better understanding the neuropathologic process of traumatic contusions induced by FPI

  20. Simultaneous measurement of glucose blood–brain transport constants and metabolic rate in rat brain using in-vivo 1H MRS

    Science.gov (United States)

    Du, Fei; Zhang, Yi; Zhu, Xiao-Hong; Chen, Wei

    2012-01-01

    Cerebral glucose consumption and glucose transport across the blood–brain barrier are crucial to brain function since glucose is the major energy fuel for supporting intense electrophysiological activity associated with neuronal firing and signaling. Therefore, the development of noninvasive methods to measure the cerebral metabolic rate of glucose (CMRglc) and glucose transport constants (KT: half-saturation constant; Tmax: maximum transport rate) are of importance for understanding glucose transport mechanism and neuroenergetics under various physiological and pathological conditions. In this study, a novel approach able to simultaneously measure CMRglc, KT, and Tmax via monitoring the dynamic glucose concentration changes in the brain tissue using in-vivo 1H magnetic resonance spectroscopy (MRS) and in plasma after a brief glucose infusion was proposed and tested using an animal model. The values of CMRglc, Tmax, and KT were determined to be 0.44±0.17 μmol/g per minute, 1.35±0.47 μmol/g per minute, and 13.4±6.8 mmol/L in the rat brain anesthetized with 2% isoflurane. The Monte-Carlo simulations suggest that the measurements of CMRglc and Tmax are more reliable than that of KT. The overall results indicate that the new approach is robust and reliable for in-vivo measurements of both brain glucose metabolic rate and transport constants, and has potential for human application. PMID:22714049

  1. Dose planning with comparison to in vivo dosimetry for epithermal neutron irradiation of the dog brain

    International Nuclear Information System (INIS)

    Seppaelae, Tiina; Auterinen, Iiro; Aschan, Carita; Seren, Tom; Benczik, Judit; Snellman, Marjatta; Huiskamp, Rene; Ramadan, Usama Abo; Kankaanranta, Leena; Joensuu, Heikki; Savolainen, Sauli

    2002-01-01

    Boron neutron capture therapy (BNCT) is an experimental type of radiotherapy, presently being used to treat glioblastoma and melanoma. To improve patient safety and to determine the radiobiological characteristics of the epithermal neutron beam of Finnish BNCT facility (FiR 1) dose-response studies were carried on the brain of dogs before starting the clinical trials. A dose planning procedure was developed and uncertainties of the epithermal neutron-induced doses were estimated. The accuracy of the method of computing physical doses was assessed by comparing with in vivo dosimetry. Individual radiation dose plans were computed using magnetic resonance images of the heads of 15 Beagle dogs and the computational model of the FiR 1 epithermal neutron beam. For in vivo dosimetry, the thermal neutron fluences were measured using Mn activation foils and the gamma-ray doses with MCP-7s type thermoluminescent detectors placed both on the skin surface of the head and in the oral cavity. The degree of uncertainty of the reference doses at the thermal neutron maximum was estimated using a dose-planning program. The estimated uncertainty (±1 standard deviation) in the total physical reference dose was ±8.9%. The calculated and the measured dose values agreed within the uncertainties at the point of beam entry. The conclusion is that the dose delivery to the tissue can be verified in a practical and reliable fashion by placing an activation dosimeter and a TL detector at the beam entry point on the skin surface with homogeneous tissues below. However, the point doses cannot be calculated correctly in the inhomogeneous area near air cavities of the head model with this type of dose-planning program. This calls for attention in dose planning in human clinical trials in the corresponding areas

  2. Acute and chronic glucocorticoid treatments regulate astrocyte-enriched mRNAs in multiple brain regions in vivo

    Directory of Open Access Journals (Sweden)

    Bradley S. Carter

    2013-08-01

    Full Text Available Previous studies have primarily interpreted gene expression regulation by glucocorticoids in the brain in terms of impact on neurons; however, less is known about the corresponding impact of glucocorticoids on glia and specifically astrocytes in vivo. Recent microarray experiments have identified glucocorticoid-sensitive mRNAs in primary astrocyte cell culture, including a number of mRNAs that have reported astrocyte-enriched expression patterns relative to other brain cell types. Here, we have tested whether elevations of glucocorticoids regulate a subset of these mRNAs in vivo following acute and chronic corticosterone exposure in adult mice. Acute corticosterone exposure was achieved by a single injection of 10 mg/kg corticosterone, and tissue samples were harvested two hours post-injection. Chronic corticosterone exposure was achieved by administering 10 mg/mL corticosterone via drinking water for two weeks. Gene expression was then assessed in two brain regions associated with glucocorticoid action (prefrontal cortex and hippocampus by qPCR and by in situ hybridization. The majority of measured mRNAs regulated by glucocorticoids in astrocytes in vitro were similarly regulated by acute and/or chronic glucocorticoid exposure in vivo. In addition, the expression levels for mRNAs regulated in at least one corticosterone exposure condition (acute/chronic demonstrated moderate positive correlation between the two conditions by brain region. In situ hybridization analyses suggest that select mRNAs are regulated by chronic corticosterone exposure specifically in astroctyes based on (1 similar general expression patterns between corticosterone-treated and vehicle-treated animals and (2 similar expression patterns to the pan-astrocyte marker Aldh1l1. Our findings demonstrate that glucocorticoids regulate astrocyte-enriched mRNAs in vivo and suggest that glucocorticoids regulate gene expression in the brain in a cell type-dependent fashion.

  3. Interaction of D-LSD with binding sites in brain: a study in vivo and in vitro

    International Nuclear Information System (INIS)

    Ebersole, B.L.J.

    1985-01-01

    The localization of [ 3 H]-d-lysergic acid diethylamide ([ 3 H]LSD) binding sites in the mouse brain was compared in vivo and in vitro. Radioautography of brain sections incubated with [ 3 H]LSD in vitro revealed substantial specific [ 3 H]LSD binding in cortical layers III-IV and areas CA1 and dentate gyrus in hippocampus. In contrast, in brain sections from animals that received [ 3 H]LSD in vivo, binding in hippocampus was scant and diffuse, although the pattern of labeling in cortex was similar to that seen in vitro. The low specific binding in hippocampus relative to cortex was confirmed by homogenate filtration studies of brain areas from mice that received injections of [ 3 H]LSD. Time-course studies established that peak specific binding at ten minutes was the same in cortex and hippocampus. At all times, binding in hippocampus was about one-third of that in cortex; in contrast, the concentration of free [ 3 H]LSD did not vary between regions. This finding was unexpected, because binding studies in vitro in membrane preparations indicated that the density and affinity of [ 3 H]LSD binding sites were similar in both brain regions. Saturation binding studies in vivo showed that the lower amount of [ 3 H]LSD binding in hippocampus was attributable to a lower density of sites labeled by [ 3 H]LSD. The pharmacological identify of [ 3 H]LSD binding sites in vivo may be relevant to the hallucinogenic properties of LSD and of other related hallucinogens

  4. Effectiveness of Interventions to Address Visual and Visual-Perceptual Impairments to Improve Occupational Performance in Adults With Traumatic Brain Injury: A Systematic Review.

    Science.gov (United States)

    Berger, Sue; Kaldenberg, Jennifer; Selmane, Romeissa; Carlo, Stephanie

    2016-01-01

    Visual and visual-perceptual impairments occur frequently with traumatic brain injury (TBI) and influence occupational performance. This systematic review examined the effectiveness of interventions within the scope of occupational therapy to improve occupational performance for adults with visual and visual-perceptual impairments as a result of TBI. Medline, PsycINFO, CINAHL, OTseeker, and the Cochrane Database of Systematic Reviews were searched, and 66 full text articles were reviewed. Sixteen articles were included in the review. Strong evidence supports the use of scanning, limited evidence supports the use of adaptive strategies, and mixed evidence supports the use of cognitive interventions to improve occupational performance for adults with TBI. Evidence related to vision therapy varies on the basis of the specific intervention implemented. Although the strength of the research varied, implications are discussed for practice, education, and research. Copyright © 2016 by the American Occupational Therapy Association, Inc.

  5. Knowledge of Mild Traumatic Brain Injury: Effects of age, locality, occupation, media and sports participation

    Directory of Open Access Journals (Sweden)

    2015-09-01

    Results: Misconceptions about TBI were reported by participants, irrespective of gender, locality, occupation, or history of sports participation. There were no significant differences in knowledge scores across these demographic groups. In particular, healthcare and education workers did not score any higher than other occupations. At least 40% of respondents answered either incorrectly or “I don’t know” on items related to gender differences, the utility of neuroimaging, and patient insight into their impairments. For those in non-medical, professional occupations, the older they were the less they knew about TBI (r = -.299, p = 0.009. In contrast, a positive correlation (r = 0.268, p = 0.018 was found between age and TBI knowledge for workers in healthcare or education. Conclusions: Misconceptions about TBI are present in Australia and are consistent across genders, localities, occupations and sport participation groups. A concern is that risk for misconceptions is not lower in healthcare or education professions. This suggests that professional development for groups most likely to be the frontline referral resources and supports for head injured children and adults may require further training.

  6. Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo.

    Directory of Open Access Journals (Sweden)

    Kuan Zhang

    Full Text Available Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG of the hippocampus and the sub-ventricular zone (SVZ of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCsin vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr and DG (approximately 10 Torr were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr. Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain.

  7. In Vivo Detection of Perinatal Brain Metabolite Changes in a Rabbit Model of Intrauterine Growth Restriction (IUGR.

    Directory of Open Access Journals (Sweden)

    Rui V Simões

    Full Text Available Intrauterine growth restriction (IUGR is a risk factor for abnormal neurodevelopment. We studied a rabbit model of IUGR by magnetic resonance imaging (MRI and spectroscopy (MRS, to assess in vivo brain structural and metabolic consequences, and identify potential metabolic biomarkers for clinical translation.IUGR was induced in 3 pregnant rabbits at gestational day 25, by 40-50% uteroplacental vessel ligation in one horn; the contralateral horn was used as control. Fetuses were delivered at day 30 and weighted. A total of 6 controls and 5 IUGR pups underwent T2-w MRI and localized proton MRS within the first 8 hours of life, at 7T. Changes in brain tissue volumes and respective contributions to each MRS voxel were estimated by semi-automated registration of MRI images with a digital atlas of the rabbit brain. MRS data were used for: (i absolute metabolite quantifications, using linear fitting; (ii local temperature estimations, based on the water chemical shift; and (iii classification, using spectral pattern analysis.Lower birth weight was associated with (i smaller brain sizes, (ii slightly lower brain temperatures, and (iii differential metabolite profile changes in specific regions of the brain parenchyma. Specifically, we found estimated lower levels of aspartate and N-acetylaspartate (NAA in the cerebral cortex and hippocampus (suggesting neuronal impairment, and higher glycine levels in the striatum (possible marker of brain injury. Our results also suggest that the metabolic changes in cortical regions are more prevalent than those detected in hippocampus and striatum.IUGR was associated with brain metabolic changes in vivo, which correlate well with the neurostructural changes and neurodevelopment problems described in IUGR. Metabolic parameters could constitute non invasive biomarkers for the diagnosis and abnormal neurodevelopment of perinatal origin.

  8. Adaptive Focusing For Ultrasonic Transcranial Brain Therapy: First In Vivo Investigation On 22 Sheep

    Science.gov (United States)

    Pernot, Mathieu; Aubry, Jean-François; Tanter, Mickael; Boch, Anne Laure; Kujas, Michelle; Fink, Mathias

    2005-03-01

    A high power prototype dedicated to trans-skull therapy has been tested in vivo on 22 sheep. The array is made of 300 high power transducers working at 1MHz central frequency and is able to achieve 400 bars at focus in water during five seconds with a 50% percent duty cycle. In the first series of experiments, 10 sheep were treated and sacrificed immediately after treatment. A complete craniotomy was performed on half of the treated animal models in order to get a reference model. On the other half, minimally invasive surgery has been performed: a hydrophone was inserted at a given target location inside the brain through a craniotomy of a few mm2. A time reversal experiment was then conducted through the skull bone with the therapeutic array to treat the targeted point. Thanks to the high power technology of the prototype, trans-skull adaptive treatment could be achieved. In a second series of experiments, 12 animals were divided into three groups and sacrificed respectively one, two or three weeks after treatment. Finally, Magnetic Resonance Imaging and histological examination were performed to confirm tissue damage.

  9. Cortical damage following traumatic brain injury evaluated by iomazenil SPECT and in vivo microdialysis.

    Science.gov (United States)

    Koizumi, Hiroyasu; Fujisawa, Hirosuke; Suehiro, Eiichi; Iwanaga, Hideyuki; Nakagawara, Jyoji; Suzuki, Michiyasu

    2013-01-01

    [(123)I] iomazenil (IMZ) single photon emission computed tomography (SPECT) has been reported to be a useful marker of neuronal integrity. We evaluated cortical damage following traumatic brain injury (TBI) with IMZ SPECT at the acute stage. After conventional therapy for a cranial trauma, an IMZ SPECT re-evaluation was performed at the chronic stage. A reduction in IMZ uptake in the location of cerebral contusions was observed during the TBI acute phase; however, images of IMZ SPECT obtained during the chronic phase showed that areas with decreased IMZ distribution were remarkably reduced compared with those obtained during the acute phase. As a result of in vivo microdialysis study, the extracellular levels of glutamate in the cortex, where decreased IMZ distribution was shown during the acute phase, were increased during the 168-h monitoring period. During the chronic phase, IMZ uptake in the region with the microdialysis probes was recovered. The results suggest that this reduction in IMZ uptake might not be a sign of irreversible tissue damage in TBI.

  10. Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in nonanesthetized rat

    NARCIS (Netherlands)

    Wong, Y.C.; Ilkova, T.I.; Wijk, van R.C.; Hartman, R.J.; Lange, de E.C.M.

    2018-01-01

    BACKGROUND: Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to

  11. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences

    Science.gov (United States)

    Zhu, Xiao-Hong; Lu, Ming; Lee, Byeong-Yeul; Ugurbil, Kamil; Chen, Wei

    2015-01-01

    NAD is an essential metabolite that exists in NAD+ or NADH form in all living cells. Despite its critical roles in regulating mitochondrial energy production through the NAD+/NADH redox state and modulating cellular signaling processes through the activity of the NAD+-dependent enzymes, the method for quantifying intracellular NAD contents and redox state is limited to a few in vitro or ex vivo assays, which are not suitable for studying a living brain or organ. Here, we present a magnetic resonance (MR) -based in vivo NAD assay that uses the high-field MR scanner and is capable of noninvasively assessing NAD+ and NADH contents and the NAD+/NADH redox state in intact human brain. The results of this study provide the first insight, to our knowledge, into the cellular NAD concentrations and redox state in the brains of healthy volunteers. Furthermore, an age-dependent increase of intracellular NADH and age-dependent reductions in NAD+, total NAD contents, and NAD+/NADH redox potential of the healthy human brain were revealed in this study. The overall findings not only provide direct evidence of declined mitochondrial functions and altered NAD homeostasis that accompany the normal aging process but also, elucidate the merits and potentials of this new NAD assay for noninvasively studying the intracellular NAD metabolism and redox state in normal and diseased human brain or other organs in situ. PMID:25730862

  12. Effect of aging on phosphate metabolites of rat brain as revealed by the in vivo and in vitro 31P NMR measurements

    International Nuclear Information System (INIS)

    Liu, Hsiuchih; Chi, Chinwen; Liu, Tsungyun; Liu, Lianghui; Luh, Wenming; Hsieh, Changhuain; Wu, Wenguey

    1991-01-01

    Changes of phosphate metabolism in brains of neonate, weaning and adult rats were compared using both in vivo and in vitro nuclear magnetic resonance spectra. Ratios of phosphocreatine/nucleoside triphosphate (PCr/NTP) were the same in neonatal brain in both in vivo and in vitro studies, but not in weaning and adult brains. This discrepancy may have resulted from extended cerebral hypoxia due to slowed freezing of the brain by the increased skull thickness and brain mass in the weaning and adult rats. Variations of in vitro extraction condition for this age-related study may lead to systematic errors in the adult rats. Nevertheless, the phosphomonoester/nucleoside triphosphate (PME/NTP) ratios in extracts of brain from neonatal rats were higher than those obtained in vivo. In addition, the glycerophosphorylethanolamine plus glycerophosphorylcholine/nucleoside triphosphate (GPE+GPC/NTP) ratios, which were not measurable in vivo, showed age-dependent increase in extracts of rat brain. Some of the phosphomonoester and phosphodiester molecules in rat brain may be undetectable in in vivo NMR analysis because of their interaction with cellular components. The total in vitro GPE and GPC concentration in brain from neonatal rat was estimated to be 0.34 mmole/g wet tissue

  13. Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Josef Jampilek

    2015-01-01

    Full Text Available The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics, which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain.

  14. Preparation of silica nanoparticles loaded with nootropics and their in vivo permeation through blood-brain barrier.

    Science.gov (United States)

    Jampilek, Josef; Zaruba, Kamil; Oravec, Michal; Kunes, Martin; Babula, Petr; Ulbrich, Pavel; Brezaniova, Ingrid; Opatrilova, Radka; Triska, Jan; Suchy, Pavel

    2015-01-01

    The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics), which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials) by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain.

  15. In vivo quantification of brain metabolites by 1H-MRS using water as an internal standard

    DEFF Research Database (Denmark)

    Christiansen, P; Henriksen, O; Stubgaard, M

    1993-01-01

    in quantification of N-acetyl aspartate (NAA) concentration was about 1-2 mM (6-12%). Also in vivo a good linearity between water signal and selected voxel size was seen. The same was true for the studied metabolites, N-acetyl aspartate (NAA), creatine/phosphocreatine (Cr/PCr), and choline (Cho). Calculated average...... concentrations of NAA, Cr/PCr, and Cho in the occipital lobe of the brain in five healthy volunteers were (mean +/- 1 SD) 11.6 +/- 1.3 mM, 7.6 +/- 1.4 mM, and 1.7 +/- 0.5 mM. The results indicate that the method presented offers reasonable estimation of metabolite concentrations in the brain in vivo...

  16. High Field In Vivo 13C Magnetic Resonance Spectroscopy of Brain by Random Radiofrequency Heteronuclear Decoupling and Data Sampling

    Science.gov (United States)

    Li, Ningzhi; Li, Shizhe; Shen, Jun

    2017-06-01

    In vivo 13C magnetic resonance spectroscopy (MRS) is a unique and effective tool for studying dynamic human brain metabolism and the cycling of neurotransmitters. One of the major technical challenges for in vivo 13C-MRS is the high radio frequency (RF) power necessary for heteronuclear decoupling. In the common practice of in vivo 13C-MRS, alkanyl carbons are detected in the spectra range of 10-65ppm. The amplitude of decoupling pulses has to be significantly greater than the large one-bond 1H-13C scalar coupling (1JCH=125-145 Hz). Two main proton decoupling methods have been developed: broadband stochastic decoupling and coherent composite or adiabatic pulse decoupling (e.g., WALTZ); the latter is widely used because of its efficiency and superb performance under inhomogeneous B1 field. Because the RF power required for proton decoupling increases quadratically with field strength, in vivo 13C-MRS using coherent decoupling is often limited to low magnetic fields (protons via weak long-range 1H-13C scalar couplings, which can be decoupled using low RF power broadband stochastic decoupling. Recently, the carboxylic/amide 13C-MRS technique using low power random RF heteronuclear decoupling was safely applied to human brain studies at 7T. Here, we review the two major decoupling methods and the carboxylic/amide 13C-MRS with low power decoupling strategy. Further decreases in RF power deposition by frequency-domain windowing and time-domain random under-sampling are also discussed. Low RF power decoupling opens the possibility of performing in vivo 13C experiments of human brain at very high magnetic fields (such as 11.7T), where signal-to-noise ratio as well as spatial and temporal spectral resolution are more favorable than lower fields.

  17. Effectiveness of Occupation- and Activity-Based Interventions to Improve Everyday Activities and Social Participation for People With Traumatic Brain Injury: A Systematic Review.

    Science.gov (United States)

    Powell, Janet M; Rich, Timothy J; Wise, Elizabeth K

    2016-01-01

    This systematic review presents research on the effectiveness of occupation- and activity-based interventions to improve everyday activities and areas of occupation and social participation for people with traumatic brain injury (TBI). Nineteen studies identified through a comprehensive database search were reviewed and synthesized into five themes: (1) multidisciplinary and interdisciplinary treatment approaches, (2) community-based rehabilitation programs, (3) treatment approaches using client-centered goals and relevant contexts, (4) social skills training and peer mentoring interventions, and (5) community mobility interventions. Evidence supports the use of multidisciplinary and interdisciplinary approaches across a variety of settings, with no single treatment approach or setting clearly superior to another. The specific contributions of occupational therapy practitioners and the nature of occupational therapy interventions have not been well studied, making it difficult to determine the extent to which occupation- and activity-based interventions provided by occupational therapy practitioners improve occupational performance and social participation after TBI. Copyright © 2016 by the American Occupational Therapy Association, Inc.

  18. A close look at brain dynamics: cells and vessels seen by in vivo two-photon microscopy.

    Science.gov (United States)

    Fumagalli, Stefano; Ortolano, Fabrizio; De Simoni, Maria-Grazia

    2014-10-01

    The cerebral vasculature has a unique role in providing a constant supply of oxygen and nutrients to ensure normal brain functions. Blood vessels that feed the brain are far from being simply channels for passive transportation of fluids. They form complex structures made up of different cell types. These structures regulate blood supply, local concentrations of O2 and CO2, transport of small molecules, trafficking of plasma cells and fine cerebral functions in normal and diseased brains. Until few years ago, analysis of these functions has been typically based on post mortem techniques, whose interpretation is limited by the need for tissue processing at specific times. For a reliable and effective picture of the dynamic processes in the central nervous system, real-time information in vivo is required. There are now few in vivo systems, among which two-photon microscopy (2-PM) is a truly innovative tool for studying the brain. 2-PM has been used to dissect specific aspects of vascular and immune cell dynamics in the context of neurological diseases, providing exciting results that could not have been obtained with conventional methods. This review summarizes the latest findings on vascular and immune system action in the brain, with particular focus on the dynamic responses after ischemic brain injury. 2-PM has helped define the hierarchical architecture of the brain vasculature, the dynamic interaction between the vasculature and immune cells recruited to lesion sites, the effects of blood flow on neuronal and microglial activity and the ability of cells of the neurovascular unit to regulate blood flow. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Intranasal brain-targeted clonazepam polymeric micelles for immediate control of status epilepticus: in vitro optimization, ex vivo determination of cytotoxicity, in vivo biodistribution and pharmacodynamics studies.

    Science.gov (United States)

    Nour, Samia A; Abdelmalak, Nevine S; Naguib, Marianne J; Rashed, Hassan M; Ibrahim, Ahmed B

    2016-11-01

    Clonazepam (CZ) is an anti-epileptic drug used mainly in status epilepticus (SE). The drug belongs to Class II according to BCS classification with very limited solubility and high permeability and it suffers from extensive first-pass metabolism. The aim of the present study was to develop CZ-loaded polymeric micelles (PM) for direct brain delivery allowing immediate control of SE. PM were prepared via thin film hydration (TFH) technique adopting a central composite face-centered design (CCFD). The seventeen developed formulae were evaluated in terms of entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and in vitro release. For evaluating the in vivo behavior of the optimized formula, both biodistrbution using 99m Tc-radiolabeled CZ and pharmacodynamics studies were done in addition to ex vivo cytotoxicty. At a drug:Pluronic® P123:Pluronic® L121 ratio of 1:20:20 (PM7), a high EE, ZP, Q8h, and a low PDI was achieved. The biodistribution studies revealed that the optimized formula had significantly higher drug targeting efficiency (DTE = 242.3%), drug targeting index (DTI = 144.25), and nose-to-brain direct transport percentage (DTP = 99.30%) and a significant prolongation of protection from seizures in comparison to the intranasally administered solution with minor histopathological changes. The declared results reveal the ability of the developed PM to be a strong potential candidate for the emergency treatment of SE.

  20. Simultaneous recording of fluorescence and electrical signals by photometric patch electrode in deep brain regions in vivo.

    Science.gov (United States)

    Hirai, Yasuharu; Nishino, Eri; Ohmori, Harunori

    2015-06-01

    Despite its widespread use, high-resolution imaging with multiphoton microscopy to record neuronal signals in vivo is limited to the surface of brain tissue because of limited light penetration. Moreover, most imaging studies do not simultaneously record electrical neural activity, which is, however, crucial to understanding brain function. Accordingly, we developed a photometric patch electrode (PME) to overcome the depth limitation of optical measurements and also enable the simultaneous recording of neural electrical responses in deep brain regions. The PME recoding system uses a patch electrode to excite a fluorescent dye and to measure the fluorescence signal as a light guide, to record electrical signal, and to apply chemicals to the recorded cells locally. The optical signal was analyzed by either a spectrometer of high light sensitivity or a photomultiplier tube depending on the kinetics of the responses. We used the PME in Oregon Green BAPTA-1 AM-loaded avian auditory nuclei in vivo to monitor calcium signals and electrical responses. We demonstrated distinct response patterns in three different nuclei of the ascending auditory pathway. On acoustic stimulation, a robust calcium fluorescence response occurred in auditory cortex (field L) neurons that outlasted the electrical response. In the auditory midbrain (inferior colliculus), both responses were transient. In the brain-stem cochlear nucleus magnocellularis, calcium response seemed to be effectively suppressed by the activity of metabotropic glutamate receptors. In conclusion, the PME provides a powerful tool to study brain function in vivo at a tissue depth inaccessible to conventional imaging devices. Copyright © 2015 the American Physiological Society.

  1. Assessing occupational and domestic ELF magnetic field exposure in the UK Adult Brain Tumour Study: Results of a feasibility study

    International Nuclear Information System (INIS)

    Van Tongeren, M.; Mee, T.; Whatmough, P.; Broad, L.; Mashlanyj, M.; Allen, S.; Muir, K.; McKinney, P.

    2004-01-01

    The feasibility of measuring exposure to extremely low frequency magnetic fields (ELF MF) in the UK Adult Brain Tumour Study (UKABTS) was examined. During the study, 81 individuals and 30 companies were approached with 79 individuals and 25 companies agreeing to participate. Exposure data were collected using EMDEX II dosemeters worn by the participants for 3-4 consecutive days. Data were collected over a total of 321 d, including non-occupational periods. The results showed occupational exposure to be the main determinant of overall exposure. Moderate to strong correlations were found between arithmetic mean exposure and all other metrics with the possible exception of maximum exposure. Significant differences in exposure were found between job categories with large variability in certain categories. Highest average exposures were found for security officers (arithmetic mean, AM: 0.78 μT), secretaries (AM: 0.48 μT) and dentists (AM: 0.42 μT). Welding and working near high-voltage power lines were associated with elevated exposure. In summary, acceptably precise measures of ELF MF exposure are feasible at relatively moderate cost. The results were used to develop a protocol for data collection from subjects in the UKABTS. (authors)

  2. Radiation-induced changes in human brain metabolites as studied by {sup 1}H nuclear magnetic resonance spectroscopy in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Usenius, Taina; Usenius, Jussi-Pekka; Tenhunen, Mikko; Vainio, Pauli; Johansson, Risto; Soimakallio, Seppo; Kauppinen, Risto

    1995-10-15

    Purpose: External radiation therapy for brain tumors exposes healthy areas of brain to considerable doses of radiation. This may cause cognitive and psychological impairment, which indicate neuronal dysfunction. {sup 1}H-magnetic resonance spectroscopy (MRS) was used to study brain metabolites in the adjacent regions 0.5-13 years after exposure to therapeutic irradiation. Methods and Materials: Eight patients with irradiated brain tumors were examined by means of in vivo{sup 1}H-MRS using a point-resolved spectroscopy (PRESS) sequence with echo times of 60 or 270 ms. The metabolites were quantified by using brain water concentration as internal reference. The volume of interest (VOI) was positioned in irradiated brain areas excluding, however, scar and recurrent tumor. The respective radiation doses were measured based on radiation therapy plans, simulator films, and localization MR images. Results: The concentration of the neuron-specific metabolite N-acetyl-l-aspartate (NAA) was 13.2 {+-} 1.4 mmol/l in controls, whereas it was reduced in the brains of treated patients to 8.6 {+-} 0.9 mmol/l (total radiation dose 59-62 Gy). Concentrations of creatine and choline-containing compounds were unchanged. The T2 of water was longer in irradiated than in unexposed brain areas. Conclusion: Therapeutic brain irradiation causes neuronal damage, which is reflected by reduction of N-acetyl-l-aspartate (NAA) concentrations. {sup 1}H-MRS could serve clinically as a means of evaluating adverse effects in the central nervous system, enabling intervention and rehabilitation.

  3. Radiation-induced changes in human brain metabolites as studied by 1H nuclear magnetic resonance spectroscopy in vivo

    International Nuclear Information System (INIS)

    Usenius, Taina; Usenius, Jussi-Pekka; Tenhunen, Mikko; Vainio, Pauli; Johansson, Risto; Soimakallio, Seppo; Kauppinen, Risto

    1995-01-01

    Purpose: External radiation therapy for brain tumors exposes healthy areas of brain to considerable doses of radiation. This may cause cognitive and psychological impairment, which indicate neuronal dysfunction. 1 H-magnetic resonance spectroscopy (MRS) was used to study brain metabolites in the adjacent regions 0.5-13 years after exposure to therapeutic irradiation. Methods and Materials: Eight patients with irradiated brain tumors were examined by means of in vivo 1 H-MRS using a point-resolved spectroscopy (PRESS) sequence with echo times of 60 or 270 ms. The metabolites were quantified by using brain water concentration as internal reference. The volume of interest (VOI) was positioned in irradiated brain areas excluding, however, scar and recurrent tumor. The respective radiation doses were measured based on radiation therapy plans, simulator films, and localization MR images. Results: The concentration of the neuron-specific metabolite N-acetyl-l-aspartate (NAA) was 13.2 ± 1.4 mmol/l in controls, whereas it was reduced in the brains of treated patients to 8.6 ± 0.9 mmol/l (total radiation dose 59-62 Gy). Concentrations of creatine and choline-containing compounds were unchanged. The T2 of water was longer in irradiated than in unexposed brain areas. Conclusion: Therapeutic brain irradiation causes neuronal damage, which is reflected by reduction of N-acetyl-l-aspartate (NAA) concentrations. 1 H-MRS could serve clinically as a means of evaluating adverse effects in the central nervous system, enabling intervention and rehabilitation

  4. Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT{sub 4} receptors with SPET

    Energy Technology Data Exchange (ETDEWEB)

    Pike, Victor W. [MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, W12 0NN, London (United Kingdom); PET Radiopharmaceutical Sciences Section, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, MD 20892-1003, Bethesda (United States); Halldin, Christer; Nobuhara, Kenji; Swahn, Carl-Gunnar; Karlsson, Per; Olsson, Hans; Larsson, Stig; Schnell, Per-Olof; Farde, Lars [Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska Hospital, 17176, Stockholm (Sweden); Hiltunen, Julka [MAP Medical Technologies, Oy, Tikkakoski (Finland); Mulligan, Rachel S. [MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, W12 0NN, London (United Kingdom); Institute of Psychiatry, SE 8AF, De Crespigny Park, Denmark Hill, London (United Kingdom); Centre for PET, Austin and Repatriation Medical Centre, Studley Road, Melbourne VIC 3084 (Australia); Hume, Susan P.; Hirani, Ella [MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, W12 0NN, London (United Kingdom); Imaging Research Solutions Ltd., Cyclotron Building, Hammersmith Hospital, Ducane Road, W12 0NN, London (United Kingdom); Whalley, Jaqueline [MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, W12 0NN, London (United Kingdom); Pilowsky, Lyn S. [Institute of Psychiatry, SE 8AF, De Crespigny Park, Denmark Hill, London (United Kingdom); Institute of Nuclear Medicine, Royal Free and University College, Medical School, Mortimer Street, W1N 8AA, London (United Kingdom); Ell, Peter J. [Institute of Nuclear Medicine, Royal Free and University College, Medical School, Mortimer Street, W1N 8AA, London (United Kingdom)

    2003-11-01

    Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT{sub 4}) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT{sub 4} receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT{sub 4} receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT{sub 4} receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [{sup 123}I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT{sub 4} receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT{sub 4} receptor antagonist, SB 204070, at 20 min before [{sup 123}I]SB 207710 injection

  5. Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Shu-Hui [Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan (China); Wen, Chih-Jen; Yen, Tzu-Chen [Animal Molecular Imaging Center, Chang Gung Memorial Hospital, Kweishan, Taoyuan 333, Taiwan (China); Al-Suwayeh, S A; Fang, Jia-You [Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh (Saudi Arabia); Chang, Hui-Wen, E-mail: fajy@mail.cgu.edu.tw [Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan 333, Taiwan (China)

    2010-10-08

    Nanostructured lipid carriers (NLCs) were prepared to investigate whether the duration of brain targeting and accumulation of drugs in the brain can be improved by intravenous delivery. NLCs were developed using cetyl palmitate as the lipid matrix, squalene as the cationic surfactant, and Pluronic F68, polysorbate 80 and polyethylene glycol as the interfacial additives. Solid lipid nanoparticles (SLNs) and lipid emulsions (LEs) were also prepared for comparison. An anti-Parkinson's drug, apomorphine, was used as the model drug. Nuclear magnetic resonance and differential scanning calorimetry showed possible interactions between the solid and liquid lipids in the inner core. The lipid nanoparticles with different compositions were characterized by mean size, zeta potential, apomorphine encapsulation and in vitro drug release. NLCs were 370-430 nm in size, which was between the sizes of the SLNs and LEs. A cationic surfactant was used to produce a positive surface charge of 42-50 mV. The base form of apomorphine was successfully entrapped by NLCs with an entrapment percentage of > 60%. The loading of apomorphine in nanoparticles resulted in a slower release behavior compared to the aqueous solution, with LEs showing the lowest release. In vivo real-time bioluminescence imaging of the rat brain revealed that NLCs could be targeted, through certain vessels, to selected brain regions. This effect was further confirmed by imaging the entire brain and brain slices. The results indicated that NLCs with moderate additives are a promising controlled-release and drug-targeting system.

  6. Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug

    International Nuclear Information System (INIS)

    Hsu, Shu-Hui; Wen, Chih-Jen; Yen, Tzu-Chen; Al-Suwayeh, S A; Fang, Jia-You; Chang, Hui-Wen

    2010-01-01

    Nanostructured lipid carriers (NLCs) were prepared to investigate whether the duration of brain targeting and accumulation of drugs in the brain can be improved by intravenous delivery. NLCs were developed using cetyl palmitate as the lipid matrix, squalene as the cationic surfactant, and Pluronic F68, polysorbate 80 and polyethylene glycol as the interfacial additives. Solid lipid nanoparticles (SLNs) and lipid emulsions (LEs) were also prepared for comparison. An anti-Parkinson's drug, apomorphine, was used as the model drug. Nuclear magnetic resonance and differential scanning calorimetry showed possible interactions between the solid and liquid lipids in the inner core. The lipid nanoparticles with different compositions were characterized by mean size, zeta potential, apomorphine encapsulation and in vitro drug release. NLCs were 370-430 nm in size, which was between the sizes of the SLNs and LEs. A cationic surfactant was used to produce a positive surface charge of 42-50 mV. The base form of apomorphine was successfully entrapped by NLCs with an entrapment percentage of > 60%. The loading of apomorphine in nanoparticles resulted in a slower release behavior compared to the aqueous solution, with LEs showing the lowest release. In vivo real-time bioluminescence imaging of the rat brain revealed that NLCs could be targeted, through certain vessels, to selected brain regions. This effect was further confirmed by imaging the entire brain and brain slices. The results indicated that NLCs with moderate additives are a promising controlled-release and drug-targeting system.

  7. 3D high spectral and spatial resolution imaging of ex vivo mouse brain

    International Nuclear Information System (INIS)

    Foxley, Sean; Karczmar, Gregory S.; Domowicz, Miriam; Schwartz, Nancy

    2015-01-01

    Purpose: Widely used MRI methods show brain morphology both in vivo and ex vivo at very high resolution. Many of these methods (e.g., T 2 * -weighted imaging, phase-sensitive imaging, or susceptibility-weighted imaging) are sensitive to local magnetic susceptibility gradients produced by subtle variations in tissue composition. However, the spectral resolution of commonly used methods is limited to maintain reasonable run-time combined with very high spatial resolution. Here, the authors report on data acquisition at increased spectral resolution, with 3-dimensional high spectral and spatial resolution MRI, in order to analyze subtle variations in water proton resonance frequency and lineshape that reflect local anatomy. The resulting information compliments previous studies based on T 2 * and resonance frequency. Methods: The proton free induction decay was sampled at high resolution and Fourier transformed to produce a high-resolution water spectrum for each image voxel in a 3D volume. Data were acquired using a multigradient echo pulse sequence (i.e., echo-planar spectroscopic imaging) with a spatial resolution of 50 × 50 × 70 μm 3 and spectral resolution of 3.5 Hz. Data were analyzed in the spectral domain, and images were produced from the various Fourier components of the water resonance. This allowed precise measurement of local variations in water resonance frequency and lineshape, at the expense of significantly increased run time (16–24 h). Results: High contrast T 2 * -weighted images were produced from the peak of the water resonance (peak height image), revealing a high degree of anatomical detail, specifically in the hippocampus and cerebellum. In images produced from Fourier components of the water resonance at −7.0 Hz from the peak, the contrast between deep white matter tracts and the surrounding tissue is the reverse of the contrast in water peak height images. This indicates the presence of a shoulder in the water resonance that is not

  8. 3D high spectral and spatial resolution imaging of ex vivo mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Foxley, Sean, E-mail: sean.foxley@ndcn.ox.ac.uk; Karczmar, Gregory S. [Department of Radiology, University of Chicago, Chicago, Illinois 60637 (United States); Domowicz, Miriam [Department of Pediatrics, University of Chicago, Chicago, Illinois 60637 (United States); Schwartz, Nancy [Department of Pediatrics, Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637 (United States)

    2015-03-15

    Purpose: Widely used MRI methods show brain morphology both in vivo and ex vivo at very high resolution. Many of these methods (e.g., T{sub 2}{sup *}-weighted imaging, phase-sensitive imaging, or susceptibility-weighted imaging) are sensitive to local magnetic susceptibility gradients produced by subtle variations in tissue composition. However, the spectral resolution of commonly used methods is limited to maintain reasonable run-time combined with very high spatial resolution. Here, the authors report on data acquisition at increased spectral resolution, with 3-dimensional high spectral and spatial resolution MRI, in order to analyze subtle variations in water proton resonance frequency and lineshape that reflect local anatomy. The resulting information compliments previous studies based on T{sub 2}{sup *} and resonance frequency. Methods: The proton free induction decay was sampled at high resolution and Fourier transformed to produce a high-resolution water spectrum for each image voxel in a 3D volume. Data were acquired using a multigradient echo pulse sequence (i.e., echo-planar spectroscopic imaging) with a spatial resolution of 50 × 50 × 70 μm{sup 3} and spectral resolution of 3.5 Hz. Data were analyzed in the spectral domain, and images were produced from the various Fourier components of the water resonance. This allowed precise measurement of local variations in water resonance frequency and lineshape, at the expense of significantly increased run time (16–24 h). Results: High contrast T{sub 2}{sup *}-weighted images were produced from the peak of the water resonance (peak height image), revealing a high degree of anatomical detail, specifically in the hippocampus and cerebellum. In images produced from Fourier components of the water resonance at −7.0 Hz from the peak, the contrast between deep white matter tracts and the surrounding tissue is the reverse of the contrast in water peak height images. This indicates the presence of a shoulder in

  9. Differential transgene expression in brain cells in vivo and in vitro from AAV-2 vectors with small transcriptional control units

    International Nuclear Information System (INIS)

    Kuegler, S.; Lingor, P.; Schoell, U.; Zolotukhin, S.; Baehr, M.

    2003-01-01

    Adeno-associated- (AAV) based vectors are promising tools for gene therapy applications in several organs, including the brain, but are limited by their small genome size. Two short promoters, the human synapsin 1 gene promoter (hSYN) and the murine cytomegalovirus immediate early promoter (mCMV), were evaluated in bicistronic AAV-2 vectors for their expression profiles in cultured primary brain cells and in the rat brain. Whereas transgene expression from the hSYN promoter was exclusively neuronal, the murine CMV promoter targeted expression mainly to astrocytes in vitro and showed weak transgene expression in vivo in retinal and cortical neurons, but strong expression in thalamic neurons. We propose that neuron specific transgene expression in combination with enhanced transgene capacity will further substantially improve AAV based vector technology

  10. An in vivo three-dimensional magnetic resonance imaging-based averaged brain collection of the neonatal piglet (Sus scrofa.

    Directory of Open Access Journals (Sweden)

    Matthew S Conrad

    Full Text Available Due to the fact that morphology and perinatal growth of the piglet brain is similar to humans, use of the piglet as a translational animal model for neurodevelopmental studies is increasing. Magnetic resonance imaging (MRI can be a powerful tool to study neurodevelopment in piglets, but many of the MRI resources have been produced for adult humans. Here, we present an average in vivo MRI-based atlas specific for the 4-week-old piglet. In addition, we have developed probabilistic tissue classification maps. These tools can be used with brain mapping software packages (e.g. SPM and FSL to aid in voxel-based morphometry and image analysis techniques. The atlas enables efficient study of neurodevelopment in a highly tractable translational animal with brain growth and development similar to humans.

  11. In vivo bioimpedance measurement of healthy and ischaemic rat brain: implications for stroke imaging using electrical impedance tomography

    International Nuclear Information System (INIS)

    Dowrick, T; Blochet, C; Holder, D

    2015-01-01

    In order to facilitate the imaging of haemorrhagic and ischaemic stroke using frequency difference electrical impedance tomography (EIT), impedance measurements of normal and ischaemic brain, and clotted blood during haemorrhage, were gathered using a four-terminal technique in an in vivo animal model, a first for ischaemic measurements. Differences of 5–10% in impedance were seen between the frequency spectrums of healthy and ischaemic brain, over the frequency range 0–3 kHz, while the spectrum of blood was predominately uniform. The implications of imaging blood/ischaemia in the brain using electrical impedance tomography are discussed, supporting the notion that it will be possible to differentiate stroke from haemorrhage. (paper)

  12. In vivo evaluation of potential Tc-99m brain perfusion agents using brain uptake index determination and biodistribution

    International Nuclear Information System (INIS)

    Rajeckas, A.J.; Watson, A.D.; Subramanyam, V.; Williams, S.J.; Belonga, B.Q.; de Nemours, E.I.D.

    1985-01-01

    In order to evaluate the pharmacological properties of various Tc-99m complexes as potential brain perfusion agents, the authors have employed both biodistribution techniques as well as modified Oldendorf procedure for the determination of the brain uptake index (BUI). A typical BUI determination involves the coinjection of 1 microcurie each of I-125 iodoantipyrine and the Tc-99m complex into the left carotid artery of a pentabarbitol anesthetized rat. The animal is sacrificed at 10 seconds; the right and left hemispheres of the brain are removed and counted for each isotope in a gamma well counter. Biodistribution studies are performed using tail-vein injections in unanesthetized rats. In the evaluation of a series of Tc-99m N/sub 2/S/sub 2/ (diamine dithiol) complexes, they have observed that compounds with a low BUI (less than 50) also have a low brain concentration (less than 1% ID) at 30 seconds post injection

  13. Recombinant Adeno-Associated Virus-Mediated microRNA Delivery into the Postnatal Mouse Brain Reveals a Role for miR-134 in Dendritogenesis in Vivo

    DEFF Research Database (Denmark)

    Christensen, Mette; Larsen, Lars A; Kauppinen, Sakari

    2010-01-01

    delivery of microRNAs in vivo by use of recombinant adeno-associated virus (rAAV). rAAV-mediated overexpression of miR-134 in neurons of the postnatal mouse brain provided evidence for a negative role of miR-134 in dendritic arborization of cortical layer V pyramidal neurons in vivo, thereby confirming...

  14. In vivo continuous and simultaneous monitoring of brain energy substrates with a multiplex amperometric enzyme-based biosensor device.

    Science.gov (United States)

    Cordeiro, C A; de Vries, M G; Ngabi, W; Oomen, P E; Cremers, T I F H; Westerink, B H C

    2015-05-15

    Enzyme-based amperometric biosensors are widely used for monitoring key biomarkers. In experimental neuroscience there is a growing interest in in vivo continuous and simultaneous monitoring of metabolism-related biomarkers, like glucose, lactate and pyruvate. The use of multiplex biosensors will provide better understanding of brain energy metabolism and its role in neuropathologies such as diabetes, ischemia, and epilepsy. We have developed and characterized an implantable multiplex microbiosensor device (MBD) for simultaneous and continuous in vivo monitoring of glucose, lactate, and pyruvate. First, we developed and characterized amperometric microbiosensors for monitoring lactate and pyruvate. In vitro evaluation allowed us to choose the most suitable biosensors for incorporation into the MBD, along with glucose and background biosensors. Fully assembled MBDs were characterized in vitro. The calculated performance parameters (LOD, LR, LRS, IMAX and appKM) showed that the multiplex MBD was highly selective and sensitive (LRS≥100 nA/mM) for each analyte and within an adequate range for in vivo application. Finally, MBDs were implanted in the mPFC of anesthetized adult male Wistar rats for in vivo evaluation. Following an equilibration period, baseline brain levels of glucose (1.3±0.2 mM), lactate (1.5±0.4 mM) and pyruvate (0.3±0.1 mM) were established. Subsequently, the MBDs recorded the responses of the animals when submitted to hyperglycemic (40% glucose i.v.) and hypoglycemic (5 U/kg insulin i.v.) challenges. Afterwards, MBDs were recalibrated to convert electrochemical readings into accurate substrate concentrations and to assess biofouling. The presented MBD can monitor simultaneously multiple biomarkers in vivo. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. A wireless beta-microprobe based on pixelated silicon for in vivo brain studies in freely moving rats

    Science.gov (United States)

    Märk, J.; Benoit, D.; Balasse, L.; Benoit, M.; Clémens, J. C.; Fieux, S.; Fougeron, D.; Graber-Bolis, J.; Janvier, B.; Jevaud, M.; Genoux, A.; Gisquet-Verrier, P.; Menouni, M.; Pain, F.; Pinot, L.; Tourvielle, C.; Zimmer, L.; Morel, C.; Laniece, P.

    2013-07-01

    The investigation of neurophysiological mechanisms underlying the functional specificity of brain regions requires the development of technologies that are well adjusted to in vivo studies in small animals. An exciting challenge remains the combination of brain imaging and behavioural studies, which associates molecular processes of neuronal communications to their related actions. A pixelated intracerebral probe (PIXSIC) presents a novel strategy using a submillimetric probe for beta+ radiotracer detection based on a pixelated silicon diode that can be stereotaxically implanted in the brain region of interest. This fully autonomous detection system permits time-resolved high sensitivity measurements of radiotracers with additional imaging features in freely moving rats. An application-specific integrated circuit (ASIC) allows for parallel signal processing of each pixel and enables the wireless operation. All components of the detector were tested and characterized. The beta+ sensitivity of the system was determined with the probe dipped into radiotracer solutions. Monte Carlo simulations served to validate the experimental values and assess the contribution of gamma noise. Preliminary implantation tests on anaesthetized rats proved PIXSIC's functionality in brain tissue. High spatial resolution allows for the visualization of radiotracer concentration in different brain regions with high temporal resolution.

  16. Cholesterol-PEG comodified poly (N-butyl) cyanoacrylate nanoparticles for brain delivery: in vitro and in vivo evaluations.

    Science.gov (United States)

    Hu, Xiao; Yang, Feifei; Liao, Yonghong; Li, Lin; Zhang, Lan

    2017-11-01

    This study investigated cholesterol-polyethylene glycol (PEG) comodified poly (ethyleneglycol)-poly (lactide) nanoparticles (CLS-PEG NPs) as a novel, biodegradable brain drug delivery system and included an evaluation of its in vitro and in vivo properties. To this end, coumarin-6 (C6), a fluorescent probe, was encapsulated into CLS-PEG NPs by an emulsion polymerization method. We reported that the use of CLS-PEG NPs led to a sustained drug release in vitro. Additionally, cell viability experiments confirmed their safety. The uptake and transport of CLS-PEG NPs, by bEnd.3 cells (an immortalized mouse brain endothelial cell line), was significantly higher than that of a control C6 solution. An investigation of the uptake mechanisms of different NP formulations demonstrated that cholesterol modifications may be the primary way to improve the efficiency of cellular uptake, wherein macropinocytosis may be the most important endocytic pathway in this process. An investigation of the transport mechanisms of CLS-PEG NPs also implicated macropinocytosis, energy and cholesterol in bEnd.3 cells lines. Following an intravenous (IV) administration to rats, pharmacokinetic experiments indicated that C6-loaded CLS-PEG NPs achieved sustained release for up to 12 h. In addition, IV delivery of CLS-PEG NPs appeared to significantly improve the ability of C6 to pass through the blood-brain barrier: the concentration of C6 found in the brain increased nearly 14.2-fold when C6 CLS-PEG NPs were used rather than a C6 solution. These in vitro and in vivo results strongly suggest that CLS-PEG NPs are a promising drug delivery system for targeting the brain, with low toxicity.

  17. Long-term exposure to nicotine markedly reduces kynurenic acid in rat brain - In vitro and ex vivo evidence

    International Nuclear Information System (INIS)

    Zielinska, Elzbieta; Kuc, Damian; Zgrajka, Wojciech; Turski, Waldemar A.; Dekundy, Andrzej

    2009-01-01

    Kynurenic acid (KYNA) is a recognized broad-spectrum antagonist of excitatory amino acid receptors with a particularly high affinity for the glycine co-agonist site of the N-methyl-D-aspartate (NMDA) receptor complex. KYNA is also a putative endogenous neuroprotectant. Recent studies show that KYNA strongly blocks α7 subtype of nicotinic acetylcholine receptors (nAChRs). The present studies were aimed at assessing effects of acute and chronic nicotine exposure on KYNA production in rat brain slices in vitro and ex vivo. In brain slices, nicotine significantly increased KYNA formation at 10 mM but not at 1 or 5 mM. Different nAChR antagonists (dihydro-β-erythroidine, methyllycaconitine and mecamylamine) failed to block the influence exerted by nicotine on KYNA synthesis in cortical slices in vitro. Effects of acute (1 mg/kg, i.p.), subchronic (10-day) and chronic (30-day) administration of nicotine in drinking water (100 μg/ml) on KYNA brain content were evaluated ex vivo. Acute treatment with nicotine (1 mg/kg i.p.) did not affect KYNA level in rat brain. The subchronic exposure to nicotine in drinking water significantly increased KYNA by 43%, while chronic exposure to nicotine resulted in a reduction in KYNA by 47%. Co-administration of mecamylamine with nicotine in drinking water for 30 days reversed the effect exerted by nicotine on KYNA concentration in the cerebral cortex. The present results provide evidence for the hypothesis of reciprocal interaction between the nicotinic cholinergic system and the kynurenine pathway in the brain.

  18. In vivo quantification by SPECT of [{sup 123}I] ADAM bound to serotonin transporters in the brains of rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Ye, X.-X. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Hwang, J.-J. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Hsieh, J.-F. [Department of Nuclear Medicine, Chi-Mei Foundation Medical Center, Yungkang City 710, Taiwan (China); Chen, J.-C. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China)]. E-mail: jcchen@ym.edu.tw; Chou, Y.-T. [Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan (China); Tu, K.-Y. [Department of Nuclear Medicine, Mackey Memorial Hospital, Taipei, Taiwan 104 (China); Wey, S.-P. [Department of Medical Imaging and Radiological Sciences, Chang-Gung University, Taoyuan, Taiwan 333 (China); Ting Gann [Institute of Nuclear Energy Research, Tao- Yuan 335, Taiwan (China)

    2004-11-01

    Background: A novel radioiodine ligand [{sup 123}I] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) has been suggested as a promising serotonin transporter (SERT) imaging agent for the central nervous system. In this study, the biodistribution of SERTs in the rabbit brain was investigated using [{sup 123}I] ADAM and mapping images of the same animal produced by both single-photon emission computed tomography (SPECT) and microautoradiography. A semiquantification method was adopted to deduce the optimum time for SPECT imaging, whereas the input for a simple fully quantitative tracer kinetic model was provided from arterial blood sampling data. Methods: SPECT imaging was performed on female rabbits postinjection of 185 MBq [{sup 123}I] ADAM. The time-activity curve obtained from the SPECT images was used to quantify the SERTs, for which the binding potential was calculated from the kinetic modeling of [{sup 123}I] ADAM. The kinetic data were analyzed by the nonlinear least squares method. The effects of the selective serotonin reuptake inhibitors fluoxetine and p-chloroamphetamine (PCA) on rabbits were also evaluated. After scanning, the same animal was sacrificed and the brain was removed for microautoradiography. Regions-of-interest were analyzed using both SPECT and microautoradiography images. The SPECT images were coregistered manually with the corresponding microautoradiography images for comparative study. Results: During the time interval 90-100 min postinjection, the peak specific binding levels in different brain regions were compared and the brain stem was shown to have the highest activity. The target-to-background ratio was 1.89{+-}0.02. Similar studies with fluoxetine and PCA showed a background level for SERT occupation. Microautoradiography demonstrated a higher level of anatomical details of the [{sup 123}I] ADAM distribution than that obtained by SPECT imaging of the rabbit brain. Conclusion: SPECT imaging of the rabbit brain with

  19. In vivo quantification by SPECT of [123I] ADAM bound to serotonin transporters in the brains of rabbits

    International Nuclear Information System (INIS)

    Ye, X.-X.; Hwang, J.-J.; Hsieh, J.-F.; Chen, J.-C.; Chou, Y.-T.; Tu, K.-Y.; Wey, S.-P.; Ting Gann

    2004-01-01

    Background: A novel radioiodine ligand [ 123 I] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) has been suggested as a promising serotonin transporter (SERT) imaging agent for the central nervous system. In this study, the biodistribution of SERTs in the rabbit brain was investigated using [ 123 I] ADAM and mapping images of the same animal produced by both single-photon emission computed tomography (SPECT) and microautoradiography. A semiquantification method was adopted to deduce the optimum time for SPECT imaging, whereas the input for a simple fully quantitative tracer kinetic model was provided from arterial blood sampling data. Methods: SPECT imaging was performed on female rabbits postinjection of 185 MBq [ 123 I] ADAM. The time-activity curve obtained from the SPECT images was used to quantify the SERTs, for which the binding potential was calculated from the kinetic modeling of [ 123 I] ADAM. The kinetic data were analyzed by the nonlinear least squares method. The effects of the selective serotonin reuptake inhibitors fluoxetine and p-chloroamphetamine (PCA) on rabbits were also evaluated. After scanning, the same animal was sacrificed and the brain was removed for microautoradiography. Regions-of-interest were analyzed using both SPECT and microautoradiography images. The SPECT images were coregistered manually with the corresponding microautoradiography images for comparative study. Results: During the time interval 90-100 min postinjection, the peak specific binding levels in different brain regions were compared and the brain stem was shown to have the highest activity. The target-to-background ratio was 1.89±0.02. Similar studies with fluoxetine and PCA showed a background level for SERT occupation. Microautoradiography demonstrated a higher level of anatomical details of the [ 123 I] ADAM distribution than that obtained by SPECT imaging of the rabbit brain. Conclusion: SPECT imaging of the rabbit brain with [ 123 I] ADAM showed

  20. Characterization of a novel brain barrier ex vivo insect-based P-glycoprotein screening model

    DEFF Research Database (Denmark)

    Andersson, O.; Badisco, L.; Hansen, A. H.

    2014-01-01

    In earlier studies insects were proposed as suitable models for vertebrate blood–brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain b...... has the potential to act as a robust and convenient model for assessing BBB permeability in early drug discovery.......In earlier studies insects were proposed as suitable models for vertebrate blood–brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain...

  1. Autoradiographic localization of glucocorticosteriod binding sites in rat brain after in vivo injection of [3H]RU 28362

    International Nuclear Information System (INIS)

    Sarrieau, Alain; Dussaillant, Monique; Rostene, William

    1988-01-01

    The autoradiographic distribution of glucocorticosteriod binding sites in the brain of adrenalectomized rats was studied following in vivo injection of a potent synthetic glucocorticosteriod agonist [ 3 H]RU 28362. Analysis of the autoradiograms revealed a specific and dense labelling in the pyramidal cell layer of the Ammon's horn and in the granular cell layer of the dentate gyrus of the hippocampus. In the hypothalmus, the labelling was particularly high in the paraventricular nucleus (site of CRF synthesis), the arcuate, periventricular and the supraoptic nuclei as well as in the median eminence. Autoradiograms also revealed the presence of[ 3 H]RU 28362 binding sites in several brain regions including the amygdala, the pineal gland, the entorhinal cortex, the interpeduncular, interfascicular and dorsal raphe nuclei, the central grey and the substantia nigra suggesting possible effects of glucocorticosteriods in these structures (author)

  2. Nonviral gene therapy in vivo with PAM-RG4/apoptin as a potential brain tumor therapeutic.

    Science.gov (United States)

    An, Songhie; Nam, Kihoon; Choi, Sunghyun; Bai, Cheng Z; Lee, Yan; Park, Jong-Sang

    2013-01-01

    Glioma is still one of the most complicated forms of brain tumor to remove completely due to its location and the lack of an efficient means to specifically eliminate tumor cells. For these reasons, this study has examined the effectiveness of a nonviral gene therapy approach utilizing a tumor-selective killer gene on a brain tumor xenograft model. The therapeutic apoptin gene was recombined into the JDK plasmid and delivered into human brain tumor cells (U87MG) by using a polyamidoamine dendrimer with an arginine surface (PAM-RG4). Studies in vitro showed that the PAM-RG4/apoptin plasmid polyplex exhibited a particularly high transfection activity of .40%. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, 4',6-Diamidino-2-phenylindole (DAPI) TUNEL assay, DAPI staining, and caspase-3 activity assay verified that the tumor cells had undergone apoptosis induced by apoptin. For in vivo studies, the polyplex was injected into tumors, which were induced by injecting U87MG cells intradermally into nude mice. Based on hematoxylin and eosin staining, epidermal growth factor receptor immunohistochemistry results and tumor volume measurement results, tumor growth was effectively inhibited and no specific edema, irritation, or other harm to the skin was observed after polyplex injection. The in vivo expression of apoptin and the induction of apoptosis were verified by reverse-transcription polymerase chain reaction analysis, TUNEL assay, and DAPI staining. The PAM-RG4/apoptin gene polyplex is a strong candidate for brain tumor therapeutics because of the synergistic effect of the carrier's high transfection efficiency (35%-40%) in glioma cells and the selective apoptosis-inducing activity of apoptin in tumor cells.

  3. Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings.

    Science.gov (United States)

    Li, Dan; Yang, Ke; Li, Jie-Si; Ke, Xi-Yu; Duan, Yu; Du, Ruo; Song, Ping; Yu, Ke-Fu; Ren, Wei; Huang, Dan; Li, Xing-Huo; Hu, Xin; Zhang, Xuan; Zhang, Qiang

    2012-01-01

    Considering the observations that linoleic acid conjugated with paclitaxel (CLA-PTX) possesses antitumor activity against brain tumors, is able to cross the blood-brain barrier, but has poor water solubility, the purpose of this study was to prepare a novel CLA-PTX microemulsion and evaluate its activity against brain tumors in vitro and in vivo. The in vitro cytotoxicity of a CLA-PTX microemulsion was investigated in C6 glioma cells. The in vivo antitumor activity of the CLA-PTX microemulsion was evaluated in tumor-bearing nude mice and rats. The pharmacokinetics of the CLA-PTX microemulsion were investigated in rats, and its safety was also evaluated in mice. The average droplet size of the CLA-PTX microemulsion was approximately 176.3 ± 0.8 nm and the polydispersity index was 0.294 ± 0.024. In vitro cytotoxicity results showed that the IC(50) of the CLA-PTX microemulsion was 1.61 ± 0.83 μM for a C6 glioma cell line, which was similar to that of free paclitaxel and CLA-PTX solution (P > 0.05). The antitumor activity of the CLA-PTX microemulsion against brain tumors was confirmed in our in vivo C6 glioma tumor-bearing nude mice as well as in a rat model. In contrast, Taxol(®) had almost no significant antitumor effect in C6 glioma tumor-bearing rats, but could markedly inhibit growth of C6 tumors in C6 glioma tumor-bearing nude mice. The pharmacokinetic results indicated that CLA-PTX in solution has a much longer circulation time and produces higher drug plasma concentrations compared with the CLA-PTX microemulsion. The results of the acute toxicity study showed that the LD(50) of CLA-PTX solution was 103.9 mg/kg. In contrast, the CLA-PTX microemulsion was well tolerated in mice when administered at doses up to 200 mg/kg. CLA-PTX microemulsion is a novel formulation with significant antitumor efficacy in the treatment of brain tumors, and is safer than CLA-PTX solution.

  4. In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain

    Directory of Open Access Journals (Sweden)

    Joo Chan-Gyu

    2009-06-01

    Full Text Available Abstract Background In vivo proton magnetic resonance spectroscopy (1H-MRS studies of HIV-infected humans have demonstrated significant metabolic abnormalities that vary by brain region, but the causes are poorly understood. Metabolic changes in the frontal cortex, basal ganglia and white matter in 18 SIV-infected macaques were investigated using MRS during the first month of infection. Results Changes in the N-acetylaspartate (NAA, choline (Cho, myo-inositol (MI, creatine (Cr and glutamine/glutamate (Glx resonances were quantified both in absolute terms and relative to the creatine resonance. Most abnormalities were observed at the time of peak viremia, 2 weeks post infection (wpi. At that time point, significant decreases in NAA and NAA/Cr, reflecting neuronal injury, were observed only in the frontal cortex. Cr was significantly elevated only in the white matter. Changes in Cho and Cho/Cr were similar across the brain regions, increasing at 2 wpi, and falling below baseline levels at 4 wpi. MI and MI/Cr levels were increased across all brain regions. Conclusion These data best support the hypothesis that different brain regions have variable intrinsic vulnerabilities to neuronal injury caused by the AIDS virus.

  5. Towards real-time communication between in vivo neurophysiological data sources and simulator-based brain biomimetic models.

    Science.gov (United States)

    Lee, Giljae; Matsunaga, Andréa; Dura-Bernal, Salvador; Zhang, Wenjie; Lytton, William W; Francis, Joseph T; Fortes, José Ab

    2014-11-01

    Development of more sophisticated implantable brain-machine interface (BMI) will require both interpretation of the neurophysiological data being measured and subsequent determination of signals to be delivered back to the brain. Computational models are the heart of the machine of BMI and therefore an essential tool in both of these processes. One approach is to utilize brain biomimetic models (BMMs) to develop and instantiate these algorithms. These then must be connected as hybrid systems in order to interface the BMM with in vivo data acquisition devices and prosthetic devices. The combined system then provides a test bed for neuroprosthetic rehabilitative solutions and medical devices for the repair and enhancement of damaged brain. We propose here a computer network-based design for this purpose, detailing its internal modules and data flows. We describe a prototype implementation of the design, enabling interaction between the Plexon Multichannel Acquisition Processor (MAP) server, a commercial tool to collect signals from microelectrodes implanted in a live subject and a BMM, a NEURON-based model of sensorimotor cortex capable of controlling a virtual arm. The prototype implementation supports an online mode for real-time simulations, as well as an offline mode for data analysis and simulations without real-time constraints, and provides binning operations to discretize continuous input to the BMM and filtering operations for dealing with noise. Evaluation demonstrated that the implementation successfully delivered monkey spiking activity to the BMM through LAN environments, respecting real-time constraints.

  6. Evaluation of drug penetration into the brain: a double study by in vivo imaging with positron emission tomography and using an in vitro model of the human blood-brain barrier

    International Nuclear Information System (INIS)

    Josserand, V.; Jego, B.; Duconge, F.; Tavitian, B.; Pelerin, H.; Ezan, E.; Mabondzo, A.; Bruin, B. de; Kuhnast, B.; Dolle, F.

    2004-01-01

    The blood brain barrier (BBB) passage of a set of radiopharmaceuticals candidates was measured both in vitro using a newly developed co-culture based model of human BBB and in vivo by positron emission tomography (PET). MATERIAL and METHODS: As an in vitro BBB model, a co-culture of primary human brain endothelial cells and primary human astrocytes was used. Dynamic PET studies were performed simultaneously on 4 anesthetized rats with the EXACT HR+ camera. Volumes of interest (VOI) were manually defined on the tomographic images in order to determine the pharmacokinetics of the compounds in various organs, including brain. The in vivo input function was measured by radioactivity counting of arterial blood samples. A two-compartment model analysis was used to compute the exchanging rate constants between blood and brain and to calculate the in vivo permeability coefficient. RESULTS: There was an excellent correlation between the in vitro and in vivo permeability coefficients (r = 0.99; p < 0.001) as well as between the in vivo distribution volume and the in vitro efflux /influx permeability coefficients ratio (r = 0.76). CONCLUSION: This double study evidenced a close relationship between the in vitro and the in vivo approaches for the assessment of the BBB passage. Hence, small animal PET imaging appeared suitable to screen drugs or radiopharmaceuticals candidates aimed at cerebral targets directly in the real-life situation in vivo. (author)

  7. Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain

    International Nuclear Information System (INIS)

    Volkow, N.D.

    1999-01-01

    The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability the authors compared the levels of DAT occupancies that they had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [ 11 C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [ 11 C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd+1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockage of DAT with an estimated ED 50 for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine

  8. In vitro and in vivo studies of Allium sativum extract against deltamethrin-induced oxidative stress in rats brain and kidney.

    Science.gov (United States)

    Ncir, Marwa; Saoudi, Mongi; Sellami, Hanen; Rahmouni, Fatma; Lahyani, Amina; Makni Ayadi, Fatma; El Feki, Abdelfattah; Allagui, Mohamed Salah

    2017-09-18

    The present study investigated the in vitro and the in vivo antioxidant capacities of Allium sativum (garlic) extract against deltamethrin-induced oxidative damage in rat's brain and kidney. The in vitro result showed that highest extraction yield was achieved with methanol (20.08%). Among the tested extracts, the methanol extract exhibited the highest total phenolic, flavonoids contents and antioxidant activity. The in vivo results showed that deltamethrin treatment caused an increase of the acetylcholinesterase level (AChE) in brain and plasma, the brain and kidney conjugated dienes and lipid peroxidation (LPO) levels as compared to control group. The antioxidant enzymes results showed that deltamethrin treatment induced a significantly decrease (p < 0.01) in brain and kidney antioxidant enzymes as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) to control group. The co-administration of garlic extract reduced the toxic effects in brain and kidney tissues induced by deltamethrin.

  9. Internalization of targeted quantum dots by brain capillary endothelial cells in vivo.

    Science.gov (United States)

    Paris-Robidas, Sarah; Brouard, Danny; Emond, Vincent; Parent, Martin; Calon, Frédéric

    2016-04-01

    Receptors located on brain capillary endothelial cells forming the blood-brain barrier are the target of most brain drug delivery approaches. Yet, direct subcellular evidence of vectorized transport of nanoformulations into the brain is lacking. To resolve this question, quantum dots were conjugated to monoclonal antibodies (Ri7) targeting the murine transferrin receptor. Specific transferrin receptor-mediated endocytosis of Ri7-quantum dots was first confirmed in N2A and bEnd5 cells. After intravenous injection in mice, Ri7-quantum dots exhibited a fourfold higher volume of distribution in brain tissues, compared to controls. Immunofluorescence analysis showed that Ri7-quantum dots were sequestered throughout the cerebral vasculature 30 min, 1 h, and 4 h post injection, with a decline of signal intensity after 24 h. Transmission electron microscopic studies confirmed that Ri7-quantum dots were massively internalized by brain capillary endothelial cells, averaging 37 ± 4 Ri7-quantum dots/cell 1 h after injection. Most quantum dots within brain capillary endothelial cells were observed in small vesicles (58%), with a smaller proportion detected in tubular structures or in multivesicular bodies. Parenchymal penetration of Ri7-quantum dots was extremely low and comparable to control IgG. Our results show that systemically administered Ri7-quantum dots complexes undergo extensive endocytosis by brain capillary endothelial cells and open the door for novel therapeutic approaches based on brain endothelial cell drug delivery. © The Author(s) 2015.

  10. A pilot study on the operationalization of the Model of Occupational Self Efficacy: A model for the reintegration of persons with brain injuries to their worker roles.

    Science.gov (United States)

    Soeker, Shaheed

    2015-01-01

    Traumatic brain injury causes functional limitations that can cause people to struggle to reintegrate in the workplace despite participating in work rehabilitation programmes. The aim of the study was to explore, and describe the experiences of individuals with Traumatic Brain Injury regarding returning to work through the use of the model of occupational self-efficacy. In the study 10 individuals who were diagnosed with a mild to moderate brain injury participated in the study. The research study was positioned within the qualitative paradigm specifically utilizing case study methodology. In order to gather data from the participants, individual interviews and participant observation techniques were used. Two themes emerged from the findings of the study theme one reflected the barriers related to the use of the model (i.e. Theme one: Effective participation in the model is affected by financial assistance). The second theme related to the enabling factors related to the use of the model (i.e. Theme two: A sense of normality). The findings of this study indicated that the Model of Occupational Self Efficacy (MOS) is a useful model to use in retraining the work skills of individual's who sustained a traumatic brain injury. The participants in this study could maintain employment in the open labour market for a period of at least 12 months and it improved their ability to accept their brain injury as well as adapt to their worker roles. The MOS also provides a framework for facilitating community integration.

  11. An ex Vivo Model for Evaluating Blood-Brain Barrier Permeability, Efflux, and Drug Metabolism

    DEFF Research Database (Denmark)

    Hellman, Karin; Aadal Nielsen, Peter; Ek, Fredrik

    2016-01-01

    , risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites...

  12. Development of positron tracer for in vivo estimation of brain MAO-B activity

    International Nuclear Information System (INIS)

    Inoue, Osamu; Tominaga, Toshiyoshi; Fukuda, Nobuo; Suzuki, Kazutoshi; Yamasaki, Toshio

    1984-01-01

    Both the specificity and the measurable range of enzyme activity of this method were found to be much dependent upon the enzymatic properties of substrate-tracer. The measurable range of brain enzyme activity was found to be from zero to the maximum value which was dependent upon two factors; the elimination rate of substratetracer from the brain (Ksub(el)) and the Vsub(max)/Ksub(m) value of substrate. The detectable range of changes in enzyme activity can be made wider by using another substrate as a tracer which has a lower Vsub(max)/Ksub(m) value or larger Ksub(el) value. The specificity can be also favorably designed by selection of substrate with various enzymatic or physico-chemical properties as a tracer. N, N-dimethyl phenylethylamine (DMPEA) was selected as a substrate-tracer for the estimation of brain MAO-B activity. Very high accumulation of radioactivity into mouse brain at 1 min after intravenous injection of 11 C-DMPEA, and a long-term retention of radioactivity in the brain were observed. 11 C-DMPEA seemed to be metabolized to 11 C-dimethylamine by brain MAO, and be trapped by the blood-brain barrier. When various dosage of 1-deprenyl (a specific MAO-B inhibitor) were pretreated, brain radioactivity at 1 hr after injection of 11 C-DMPEA significantly decreased in a dosage (1-deprenyl)-dependent way, while pretreatment with clorgyline (a specific MAO-A inhibitor) had no effect. This decrease in radioactivity might be due to the decrease of the production rate of labeled metabolite ( 11 C-dimethylamine) in the brain. The relationship between the radioactivity remaining at 1 hr after injection and MAO-B activity remaining in the brain was quite paralle. 11 C-DMPEA seems to be a specific radiotracer for the external detection of alterations in MAO-B activity in the brain with a fair sensitivity. (J.P.N.)

  13. Radioligands for brain 5-HT2 receptor imaging in vivo: why do we need them?

    International Nuclear Information System (INIS)

    Busatto, G.F.

    1996-01-01

    Recently, PET and SPET radiotracers with high specificity for 5-HT 2 receptors have been developed. These have been studied in baboons and humans with promising results, displaying a binding profile compatible with the brain distribution of 5-HT 2 receptors. It is predicted that studies with the newly developed 5-HT radioligands will substantially increase knowledge about the pharmacology of brain disorders. (orig./MG)

  14. Brain delivery of valproic acid via intranasal administration of nanostructured lipid carriers: in vivo pharmacodynamic studies using rat electroshock model

    Directory of Open Access Journals (Sweden)

    Sharareh Eskandari

    2011-02-01

    Full Text Available Sharareh Eskandari1, Jaleh Varshosaz1, Mohsen Minaiyan2, Majid Tabbakhian11Department of Pharmaceutics, 2Department of Pharmacology, School of Pharmacy and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, IranAbstract: The treatment of brain disorders is one of the greatest challenges in drug delivery because of a variety of main barriers in effective drug transport and maintaining therapeutic concentrations in the brain for a prolonged period. The objective of this study was delivery of valproic acid (VPA to the brain by intranasal route. For this purpose, nanostructured lipid carriers (NLCs were prepared by solvent diffusion method followed by ultrasonication and characterized for size, zeta potential, drug-loading percentage, and release. Six groups of rats each containing six animals received drug-loaded NLCs intraperitoneally (IP or intranasally. Brain responses were then examined by using maximal electroshock (MES. The hind limb tonic extension:flexion inhibition ratio was measured at 15-, 30-, 60-, 90-, and 120-minute intervals. The drug concentration was also measured in plasma and brain at the most protective point using gas chromatography method. The particle size of NLCs was 154 ± 16 nm with drug-loading percentage of 47% ± 0.8% and drug release of 75% ± 1.9% after 21 days. In vivo results showed that there was a significant difference between protective effects of NLCs of VPA and control group 15, 30, 60, and 90 minutes after treatment via intranasal route (P < 0.05. Similar protective effect was observed in rats treated with NLCs of VPA in intranasal route and positive control in IP route (P > 0.05. Results of drug determination in brain and plasma showed that brain:plasma concentration ratio was much higher after intranasal administration of NLCs of VPA than the positive control group (IP route. In conclusion, intranasal administration of NLCs of VPA provided a better protection

  15. Cre Fused with RVG Peptide Mediates Targeted Genome Editing in Mouse Brain Cells In Vivo.

    Science.gov (United States)

    Zou, Zhiyuan; Sun, Zhaolin; Li, Pan; Feng, Tao; Wu, Sen

    2016-12-14

    Cell penetrating peptides (CPPs) are short peptides that can pass through cell membranes. CPPs can facilitate the cellular entry of proteins, macromolecules, nanoparticles and drugs. RVG peptide (RVG hereinafter) is a 29-amino-acid CPP derived from a rabies virus glycoprotein that can cross the blood-brain barrier (BBB) and enter brain cells. However, whether RVG can be used for genome editing in the brain has not been reported. In this work, we combined RVG with Cre recombinase for bacterial expression. The purified RVG-Cre protein cut plasmids in vitro and traversed cell membranes in cultured Neuro2a cells. By tail vein-injecting RVG-Cre into Cre reporter mouse lines mTmG and Rosa26 lacZ , we demonstrated that RVG-Cre could target brain cells and achieve targeted somatic genome editing in adult mice. This direct delivery of the gene-editing enzyme protein into mouse brains with RVG is much safer than plasmid- or viral-based methods, holding promise for further applications in the treatment of various brain diseases.

  16. Radioligand binding analysis of α 2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding

    DEFF Research Database (Denmark)

    Phan, Jenny-Ann; Landau, Anne M.; Jakobsen, Steen

    2017-01-01

    We describe a novel method of kinetic analysis of radioligand binding to neuroreceptors in brain in vivo, here applied to noradrenaline receptors in rat brain. The method uses positron emission tomography (PET) of [11C]yohimbine binding in brain to quantify the density and affinity of α 2...... Inhibition Plot introduced here yielded an estimate of the volume of distribution of non-displaceable ligand in brain tissue that increased with the increase of the free fraction of the radioligand in plasma. The resulting binding potentials of the radioligand declined by 50-60% in the presence of unlabeled...

  17. Image-based in vivo assessment of targeting accuracy of stereotactic brain surgery in experimental rodent models

    Science.gov (United States)

    Rangarajan, Janaki Raman; Vande Velde, Greetje; van Gent, Friso; de Vloo, Philippe; Dresselaers, Tom; Depypere, Maarten; van Kuyck, Kris; Nuttin, Bart; Himmelreich, Uwe; Maes, Frederik

    2016-11-01

    Stereotactic neurosurgery is used in pre-clinical research of neurological and psychiatric disorders in experimental rat and mouse models to engraft a needle or electrode at a pre-defined location in the brain. However, inaccurate targeting may confound the results of such experiments. In contrast to the clinical practice, inaccurate targeting in rodents remains usually unnoticed until assessed by ex vivo end-point histology. We here propose a workflow for in vivo assessment of stereotactic targeting accuracy in small animal studies based on multi-modal post-operative imaging. The surgical trajectory in each individual animal is reconstructed in 3D from the physical implant imaged in post-operative CT and/or its trace as visible in post-operative MRI. By co-registering post-operative images of individual animals to a common stereotaxic template, targeting accuracy is quantified. Two commonly used neuromodulation regions were used as targets. Target localization errors showed not only variability, but also inaccuracy in targeting. Only about 30% of electrodes were within the subnucleus structure that was targeted and a-specific adverse effects were also noted. Shifting from invasive/subjective 2D histology towards objective in vivo 3D imaging-based assessment of targeting accuracy may benefit a more effective use of the experimental data by excluding off-target cases early in the study.

  18. Distribution of 5HT2A receptors in the human brain: Comparison of data in vivo and post mortem

    International Nuclear Information System (INIS)

    Forutan, F.; Estalji, S.; Beu, M.; Nikolaus, S.; Vosberg, H.; Mueller-Gaertner, H.W.; Larisch, R.; Hamacher, K.; Coenen, H.H.

    2002-01-01

    Aim: The study presented here firstly compars the distribution of the binding potential of the serotonin-5HT 2A receptor as measured in vivo with data of receptor density taken from literature. Secondly, the sensitivity of the method to detect gradual differences in receptor densities is evaluated. Methods: Positron emission tomography (PET) studies were carried out in 6 healthy volunteers using the selective serotonin-5HT 2A ligand 18 F-altanserin. The binding potential was quantified in 12 regions using Logan's graphical method and the equilibrium method. These data were compared to the distribution of receptor density as taken from literature. Results: The binding data in vivo correlated to autoradiography data (post mortem) with r = 0.83 (Pearson regression coefficient; p 18 F-altanserin and PET in healthy volunteers and the true autoradiographically determined distribution of 5HT 2A receptors in human brains. The in vivo method seems to be sensitive enough to detect changes in receptor density of more than 18%. (orig.)

  19. Pituitary and brain D2 receptor density measured in vitro and in vivo in EEDQ treated male rats

    International Nuclear Information System (INIS)

    Ekman, A.; Eriksson, E.

    1991-01-01

    The effect of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on dopamine D2 receptor density in rat pituitary and brain was measured using in vitro and in vivo radioligand binding techniques. In the in vitro radioligand binding experiments EEDQ was found to reduce the density (B max ) of [ 3 H]-spiperone binding sites in the striatum by 86% while in the pituitary the corresponding decrease was only 37%. The affinity (K D ) of the remaining striatal and pituitary D2 receptors was not different in EEDQ treated animals as compared to controls. When D2 receptor density was measured in vivo the effect of EEDQ was less pronounced. Thus, in rats given EEDQ the specific binding of either of the two D2 ligands [ 3 H]-raclopride or [ 3 H]-spiperone in striatum and in the limbic forebrain was reduced by 45-62%; moreover, no significant decrease in pituitary D2 receptor density was observed. The data are discussed in relation to the finding that the same dose of EEDQ that failed to influence pituitary D2 receptor density as measured in vivo effectively antagonizes the prolactin decreasing effect of the partial D2 agonist (-)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine [(-)-3-PPP

  20. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Yokokura, Masamichi; Mori, Norio; Yoshihara, Yujiro; Wakuda, Tomoyasu; Takebayashi, Kiyokazu; Iwata, Yasuhide; Nakamura, Kazuhiko [Hamamatsu University School of Medicine, Department of Psychiatry and Neurology, Hamamatsu (Japan); Yagi, Shunsuke; Ouchi, Yasuomi [Hamamatsu University School of Medicine, Laboratory of Human Imaging Research, Molecular Imaging Frontier Research Center, Hamamatsu (Japan); Yoshikawa, Etsuji [Hamamatsu Photonics K.K., Central Research Laboratory, Hamamatsu (Japan); Kikuchi, Mitsuru [Kanazawa University, Department of Psychiatry and Neurobiology, Graduate School of Medical Science, Kanazawa (Japan); Sugihara, Genichi; Suda, Shiro; Tsuchiya, Kenji J.; Suzuki, Katsuaki [Hamamatsu University School of Medicine, Research Center for Child Mental Development, Hamamatsu (Japan); Ueki, Takatoshi [Hamamatsu University School of Medicine, Department of Anatomy, Hamamatsu (Japan)

    2011-02-15

    Amyloid {beta} protein (A{beta}) is known as a pathological substance in Alzheimer's disease (AD) and is assumed to coexist with a degree of activated microglia in the brain. However, it remains unclear whether these two events occur in parallel with characteristic hypometabolism in AD in vivo. The purpose of the present study was to clarify the in vivo relationship between A{beta} accumulation and neuroinflammation in those specific brain regions in early AD. Eleven nootropic drug-naive AD patients underwent a series of positron emission tomography (PET) measurements with [{sup 11}C](R)PK11195, [{sup 11}C]PIB and [{sup 18}F]FDG and a battery of cognitive tests within the same day. The binding potentials (BPs) of [{sup 11}C](R)PK11195 were directly compared with those of [{sup 11}C]PIB in the brain regions with reduced glucose metabolism. BPs of [{sup 11}C](R)PK11195 and [{sup 11}C]PIB were significantly higher in the parietotemporal regions of AD patients than in ten healthy controls. In AD patients, there was a negative correlation between dementia score and [{sup 11}C](R)PK11195 BPs, but not [{sup 11}C]PIB, in the limbic, precuneus and prefrontal regions. Direct comparisons showed a significant negative correlation between [{sup 11}C](R)PK11195 and [{sup 11}C]PIB BPs in the posterior cingulate cortex (PCC) (p < 0.05, corrected) that manifested the most severe reduction in [{sup 18}F]FDG uptake. A lack of coupling between microglial activation and amyloid deposits may indicate that A{beta} accumulation shown by [{sup 11}C]PIB is not always the primary cause of microglial activation, but rather the negative correlation present in the PCC suggests that microglia can show higher activation during the production of A{beta} in early AD. (orig.)

  1. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease

    International Nuclear Information System (INIS)

    Yokokura, Masamichi; Mori, Norio; Yoshihara, Yujiro; Wakuda, Tomoyasu; Takebayashi, Kiyokazu; Iwata, Yasuhide; Nakamura, Kazuhiko; Yagi, Shunsuke; Ouchi, Yasuomi; Yoshikawa, Etsuji; Kikuchi, Mitsuru; Sugihara, Genichi; Suda, Shiro; Tsuchiya, Kenji J.; Suzuki, Katsuaki; Ueki, Takatoshi

    2011-01-01

    Amyloid β protein (Aβ) is known as a pathological substance in Alzheimer's disease (AD) and is assumed to coexist with a degree of activated microglia in the brain. However, it remains unclear whether these two events occur in parallel with characteristic hypometabolism in AD in vivo. The purpose of the present study was to clarify the in vivo relationship between Aβ accumulation and neuroinflammation in those specific brain regions in early AD. Eleven nootropic drug-naive AD patients underwent a series of positron emission tomography (PET) measurements with [ 11 C](R)PK11195, [ 11 C]PIB and [ 18 F]FDG and a battery of cognitive tests within the same day. The binding potentials (BPs) of [ 11 C](R)PK11195 were directly compared with those of [ 11 C]PIB in the brain regions with reduced glucose metabolism. BPs of [ 11 C](R)PK11195 and [ 11 C]PIB were significantly higher in the parietotemporal regions of AD patients than in ten healthy controls. In AD patients, there was a negative correlation between dementia score and [ 11 C](R)PK11195 BPs, but not [ 11 C]PIB, in the limbic, precuneus and prefrontal regions. Direct comparisons showed a significant negative correlation between [ 11 C](R)PK11195 and [ 11 C]PIB BPs in the posterior cingulate cortex (PCC) (p 18 F]FDG uptake. A lack of coupling between microglial activation and amyloid deposits may indicate that Aβ accumulation shown by [ 11 C]PIB is not always the primary cause of microglial activation, but rather the negative correlation present in the PCC suggests that microglia can show higher activation during the production of Aβ in early AD. (orig.)

  2. Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo.

    Science.gov (United States)

    Choi, James J; Wang, Shougang; Tung, Yao-Sheng; Morrison, Barclay; Konofagou, Elisa E

    2010-01-01

    Focused ultrasound (FUS) is hereby shown to noninvasively and selectively deliver compounds at pharmacologically relevant molecular weights through the opened blood-brain barrier (BBB). A complete examination on the size of the FUS-induced BBB opening, the spatial distribution of the delivered agents and its dependence on the agent's molecular weight were imaged and quantified using fluorescence microscopy. BBB opening in mice (n=13) was achieved in vivo after systemic administration of microbubbles and subsequent application of pulsed FUS (frequency: 1.525MHz, peak-rarefactional pressure in situ: 570 kPa) to the left murine hippocampus through the intact skin and skull. BBB-impermeant, fluorescent-tagged dextrans at three distinct molecular weights spanning over several orders of magnitude were systemically administered and acted as model therapeutic compounds. First, dextrans of 3 and 70 kDa were delivered trans-BBB while 2000 kDa dextran was not. Second, compared with 70 kDa dextran, a higher concentration of 3 kDa dextran was delivered through the opened BBB. Third, the 3 and 70 kDa dextrans were both diffusely distributed throughout the targeted brain region. However, high concentrations of 70 kDa dextran appeared more punctated throughout the targeted region. In conclusion, FUS combined with microbubbles opened the BBB sufficiently to allow passage of compounds of at least 70 kDa, but not greater than 2000 kDa into the brain parenchyma. This noninvasive and localized BBB opening technique could, thus, provide a unique means for the delivery of compounds of several magnitudes of kDa that include agents with shown therapeutic promise in vitro but whose in vivo translation has been hampered by their associated BBB impermeability. (E-mail: ek2191@columbia.edu).

  3. Rolipram depresses [{sup 3}H]2-deoxyglucose uptake in mouse brain and heart in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Ishikawa, Megumi; Hosoi, Rie; Kobayashi, Kaoru; Inoue, Osamu [Department of Medical Physics, School of Allied Health Sciences, Faculty of Medicine, Osaka University, 1-7 Yamadaoka, Suita-shi, Osaka (Japan); Nishimura, Tsunehiko [Department of Radiology, Kyoto Prefectural University of Medicine, Kyoto (Japan)

    2002-09-01

    The effects of systemic administration of rolipram, a selective phosphodiesterase type 4 inhibitor, on [{sup 3}H]2-deoxyglucose (DG) uptake in brain and peripheral tissues were examined. Rolipram significantly and dose-dependently decreased [{sup 3}H]DG uptake in brain, heart and skeletal muscle. In contrast, the radioactivity concentrations in the plasma of rolipram-treated mice were significantly higher than those of control mice at all times after injection of the tracer. In the kinetic study, the initial uptake of [{sup 3}H]DG in brain was decreased by rolipram, whereas no significant differences were observed in the uptake in heart and skeletal muscle. However, radioactivity concentrations in the brain, heart and skeletal muscle 30 min after the injection of [{sup 3}H]DG were significantly lowered by rolipram to about 60%, 10% and 10% of control values, respectively. The uptake of [{sup 13}N]ammonia in brain and heart of rolipram-treated mice was slightly decreased, which indicated that rolipram diminished both cerebral and cardiac blood flow. These results indicate that the phosphorylation process via hexokinase rather than the transport of [{sup 3}H]DG might be depressed by rolipram. Together with the previous observations that inhibition of protein kinase A (PKA) markedly enhanced [{sup 14}C]DG uptake in rat brain, these results indicate an important role of the cAMP/PKA systems in the regulation of glucose metabolism in the living brain as well as in peripheral tissues such as the heart and skeletal muscle. (orig.)

  4. [An experimental study on the Chinese lung adenocarcinoma cell clone CPA-Yang1-BR with brain metastasis potency in nude mice and in vivo imaging research].

    Science.gov (United States)

    Lei, Bei; Cao, Jie; Shen, Jie; Zhao, Lanxiang; Liang, Sheng; Meng, Qinggang; Xie, Wenhui; Yang, Shunfang

    2013-08-20

    Lung cancer is the leading cause of cancer-related death in men and women. It is also the most common cause of brain metastases. A brain metastasis model is difficult to be established because of the presence of the blood-brain barrier (BBB) and the lack of optimal methods for detecting brain metastasis in nude mice. Thus, the establishment of a Chinese lung adenocarcinoma cell line and its animal model with brain metastasis potency and in vivo research is of great significance. CPA-Yang1 cells were obtained from a patient with human lung adenocarcinoma by lentiviral vector-mediated transfection of green fluorescence protein. Intracardiac inoculation of the cells was performed in nude mice, and brain metastatic lesions were detected using micro ¹⁸F FDG-PET/CT scanners, small animal in vivo imaging system for fluorescence, radionuclide and X ray fused imaging, magnetic resonance imaging (MRI) with sense body detection, and resection. The samples were divided into two parts for cell culture and histological diagnosis. The process was repeated in vivo and in vitro for four cycles to obtain a novel cell clone, CPA-Yang1-BR. A novel cell clone, CPA-Yang1-BR, was obtained with a brain metastatic rate of 50%. The use of MRI for the detection of brain metastases has obvious advantages. An experimental Chinese lung adenocarcinoma cell clone (CPA-Yang1-BR) and its animal model with brain metastasis potency in nude mice were established. MRI with sense body or micro MRI may be used as a sensitive, accurate, and noninvasive method to detect experimental brain metastases in intact live immunodeficient mice. The results of this study may serve as a technical platform for brain metastases from lung adenocarcinoma.

  5. MRI and in vivo proton MR spectroscopy in a racemose cysticercal cyst of the brain

    International Nuclear Information System (INIS)

    Jayakumar, P.N.; Chandrashekar, H.S.; Srikanth, S.G.; Guruprasad, A.S.; Devi, B.Indira; Shankar, S.K.

    2004-01-01

    Racemose cysticercal cyst is the subarachnoid manifestation of the larvae of Taenia solium. On MRI the cysts may resemble other cystic masses. We report the magnetic resonance spectroscopy (MRS) features of a case on in vivo proton spectroscopy and discuss its role in the diagnosis of intracranial cysts of parasitic aetiology. (orig.)

  6. Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry

    Science.gov (United States)

    Ateca-Cabarga, Juan C.; Cosa, Alejandro; Pallarés, Vicente; López-Atalaya, José P.; Barco, Ángel; Canals, Santiago; Moratal, David

    2015-11-01

    The Rubinstein-Taybi Syndrome (RSTS) is a congenital disease that affects brain development causing severe cognitive deficits. In most cases the disease is associated with dominant mutations in the gene encoding the CREB binding protein (CBP). In this work, we present the first quantitative analysis of brain abnormalities in a mouse model of RSTS using magnetic resonance imaging (MRI) and two novel self-developed automated algorithms for image volumetric analysis. Our results quantitatively confirm key syndromic features observed in RSTS patients, such as reductions in brain size (-16.31%, p < 0.05), white matter volume (-16.00%, p < 0.05), and corpus callosum (-12.40%, p < 0.05). Furthermore, they provide new insight into the developmental origin of the disease. By comparing brain tissues in a region by region basis between cbp+/- and cbp+/+ littermates, we found that cbp haploinsufficiency is specifically associated with significant reductions in prosencephalic tissue, such us in the olfactory bulb and neocortex, whereas regions evolved from the embryonic rhombencephalon were spared. Despite the large volume reductions, the proportion between gray-, white-matter and cerebrospinal fluid were conserved, suggesting a role of CBP in brain size regulation. The commonalities with holoprosencephaly and arhinencephaly conditions suggest the inclusion of RSTS in the family of neuronal migration disorders.

  7. Age-related deposition of brain iron in normal adults: an in vivo susceptibility weighted imaging study

    International Nuclear Information System (INIS)

    Wang Qidong; Xu Xiaojun; Zhang Minming

    2008-01-01

    Objective: The purpose of this study was to investigate the effect of age on the iron concentration of the human brain. Methods: The brain iron level was evaluated in vivo in 78 healthy adult volunteers using a noninvasive magnetic resonance method termed susceptibility weighted imaging. The subjects were divided intothree groups due to different ages: young (22-35 years old, n=27), middle- aged (36-55 years old, n=35), and aged (56-78 years old, n=16). The phase values were measured on the corrected phase images in the globus pallidus, putamen, caudate, substantia nigra, red nucleus, thalamus and frontal white matter. The phase values of those regions measured from the subjects over than 30 years old were correlated with published values of brain iron concentration in normal adults to check the validity of the data. Then, the phase values of the three groups were tested for significant age-related differences using one-way ANOVA, followed by post hoc testing using least significant difference (LSD) procedure. Regression analysis was used to further examine age-related effects revealed by group comparisons, and to estimate the rates of age-related changes. Results: A strong negative correlation was found between the phase values and the published values of the brain iron concentration (r=-0.796, P= 0.032), which indicated that the higher the iron deposition level, the greater the negative phase values. In the putamen (F=20.115, P<0.01) and frontal white matter (F=3.536, P=0.034), significant differences were detected in the phase values of the three age groups. Linear regression analysis showed that phase values of the putamen, frontal white matter, and red nucleus decreased with age (The regression coefficients were -0.001, -0.001, and < -0.001 respectively, and the P value were all < 0.05), which indicated that the iron concentration of those brain structures increased with age. No significant age- related changes of the iron concentration were found in the

  8. In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice

    International Nuclear Information System (INIS)

    Tung, Yao-Sheng; Vlachos, Fotios; Choi, James J; Deffieux, Thomas; Selert, Kirsten; Konofagou, Elisa E

    2010-01-01

    The in vivo cavitation response associated with blood-brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity (registered) microbubbles (mean diameter range: 1.1-3.3 μm, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 μm in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity (registered) microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected without

  9. In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice

    Energy Technology Data Exchange (ETDEWEB)

    Tung, Yao-Sheng; Vlachos, Fotios; Choi, James J; Deffieux, Thomas; Selert, Kirsten; Konofagou, Elisa E, E-mail: ek2191@columbia.ed [Department of Biomedical Engineering, Columbia University, New York, NY (United States)

    2010-10-21

    The in vivo cavitation response associated with blood-brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity (registered) microbubbles (mean diameter range: 1.1-3.3 {mu}m, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 {mu}m in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity (registered) microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected

  10. In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice.

    Science.gov (United States)

    Tung, Yao-Sheng; Vlachos, Fotios; Choi, James J; Deffieux, Thomas; Selert, Kirsten; Konofagou, Elisa E

    2010-10-21

    The in vivo cavitation response associated with blood-brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity® microbubbles (mean diameter range: 1.1-3.3 µm, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 µm in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity® microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected without craniotomy in mice

  11. Development of optical neuroimaging to detect drug-induced brain functional changes in vivo

    Science.gov (United States)

    Du, Congwu; Pan, Yingtian

    2014-03-01

    Deficits in prefrontal function play a crucial role in compulsive cocaine use, which is a hallmark of addiction. Dysfunction of the prefrontal cortex might result from effects of cocaine on neurons as well as from disruption of cerebral blood vessels. However, the mechanisms underlying cocaine's neurotoxic effects are not fully understood, partially due to technical limitations of current imaging techniques (e.g., PET, fMRI) to differentiate vascular from neuronal effects at sufficiently high temporal and spatial resolutions. We have recently developed a multimodal imaging platform which can simultaneously characterize the changes in cerebrovascular hemodynamics, hemoglobin oxygenation and intracellular calcium fluorescence for monitoring the effects of cocaine on the brain. Such a multimodality imaging technique (OFI) provides several uniquely important merits, including: 1) a large field-of-view, 2) high spatiotemporal resolutions, 3) quantitative 3D imaging of the cerebral blood flow (CBF) networks, 4) label-free imaging of hemodynamic changes, 5) separation of vascular compartments (e.g., arterial and venous vessels) and monitoring of cortical brain metabolic changes, 6) discrimination of cellular (neuronal) from vascular responses. These imaging features have been further advanced in combination with microprobes to form micro-OFI that allows quantification of drug effects on subcortical brain. In addition, our ultrahigh-resolution ODT (μODT) enables 3D microangiography and quantitative imaging of capillary CBF networks. These optical strategies have been used to investigate the effects of cocaine on brain physiology to facilitate the studies of brain functional changes induced by addictive substance to provide new insights into neurobiological effects of the drug on the brain.

  12. [{sup 18}F]haloperidol binding in baboon brain in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Yousef, Khalil A; Fowler, Joanna S; Volkow, Nora D; Dewey, Stephen L; Shea, Colleen; Schlyer, David J; Gatley, S John; Logan, Jean; Wolf, Alfred P

    1996-01-01

    The binding of [{sup 18}F]haloperidol to dopamine D2 and to sigma recognition sites in baboon brain was examined using positron emission tomography (PET). Studies were performed at baseline and after treatment with either haloperidol (to evaluate saturability), (+)-butaclamol (which has specificity for dopamine D2 receptors) or (-)-butaclamol (which has specificity for sigma sites). Binding was widespread. Treatment with (-)-butaclamol had no effect, whereas (+)-butaclamol selectively reduced the uptake in striatum. Haloperidol increased the clearance rate from all brain regions. These results indicate that the binding profile of [{sup 18}F]haloperidol does not permit the selective examination of either dopamine D2 or sigma sites using PET.

  13. In vivo Brain Delivery of v-myc Overproduced Human Neural Stem Cells via the Intranasal Pathway: Tumor Characteristics in the Lung of a Nude Mouse

    Directory of Open Access Journals (Sweden)

    Eun Seong Lee

    2015-01-01

    Full Text Available We aimed to monitor the successful brain delivery of stem cells via the intranasal route and to observe the long-term consequence of the immortalized human neural stem cells in the lungs of a nude mouse model. Stably immortalized HB1.F3 human neural stem cells with firefly luciferase gene (F3-effluc were intranasally delivered to BALB/c nude mice. Bioluminescence images were serially acquired until 41 days in vivo and at 4 hours and 41 days ex vivo after intranasal delivery. Lungs were evaluated by histopathology. After intranasal delivery of F3-effluc cells, the intense in vivo signals were detected in the nasal area, migrated toward the brain areas at 4 hours (4 of 13, 30.8%, and gradually decreased for 2 days. The brain signals were confirmed by ex vivo imaging (2 of 4, 50%. In the mice with initial lung signals (4 of 9, 44.4%, the lung signals disappeared for 5 days but reappeared 2 weeks later. The intense lung signals were confirmed to originate from the tumors in the lungs formed by F3-effluc cells by ex vivo imaging and histopathology. We propose that intranasal delivery of immortalized stem cells should be monitored for their successful delivery to the brain and their tumorigenicity longitudinally.

  14. Autoradiographic analysis of the in vivo distribution of 3H-imipramine and 3H-desipramine in brain: Comparison to in vitro binding patterns

    International Nuclear Information System (INIS)

    Duncan, G.E.; Paul, I.A.; Fassberg, J.B.; Powell, K.R.; Stumpf, W.E.; Breese, G.R.

    1991-01-01

    Using high resolution autoradiographic techniques, the distribution of radioactivity in forebrain and brainstem was assessed after 4 injection of 3H-impramine or 3H-desipramine. Results were compared with regional binding of the drugs to brain sections in vitro. Similar topographic binding of 3H-imipramine and 3H-desipramine was observed in vitro among brain regions, except in the paraventricular nucleus of the hypothalamus and locus coeruleus, where binding was greater for 3H-desipramine. For both 3H-desipramine and 3H-imipramine, some brain regions that exhibited high binding in vitro also showed high accumulation after in vivo injection. However, certain regions that contained high densities of binding sites for the antidepressant drugs as measured by in vitro binding showed very low accumulation of radioactivity after in vivo treatment. Such regions included the dentate gyrus of the hippocampus, layer 1 of piriform cortex, caudate-putamen, pontine and midbrain central gray, and cerebellar granular layer. Compared to in vitro binding of the drugs, the distribution of imipramine and desipramine in vivo appears more anatomically selective. For imipramine, primary sites of action in vivo, as indicated by the topographic distribution in brain, appear to be the locus coeruleus, hippocampus, lateral septal nucleus, and amygdala. For desipramine, the greatest accumulation in vivo was found in the locus coeruleus, paraventricular nucleus of the hypothalamus, and anterior thalamic nuclei

  15. Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [(11)C]MADAM PET study.

    Science.gov (United States)

    Finnema, Sjoerd J; Halldin, Christer; Bang-Andersen, Benny; Bundgaard, Christoffer; Farde, Lars

    2015-11-01

    A number of serotonin receptor positron emission tomography (PET) radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment. The cross-species differential SSRI effect may be partly explained by serotonin transporter (SERT) occupancy in monkey brain being higher than is clinically relevant. We here determine SERT occupancy after single doses of escitalopram or citalopram by conducting PET measurements with [(11)C]MADAM in monkeys. Relationships between dose, plasma concentration and SERT occupancy were estimated by one-site binding analyses. Binding affinity was expressed as dose (ID50) or plasma concentration (K i) where 50 % SERT occupancy was achieved. Estimated ID50 and K i values were 0.020 mg/kg and 9.6 nmol/L for escitalopram and 0.059 mg/kg and 9.7 nmol/L for citalopram, respectively. Obtained K i values are comparable to values reported in humans. Escitalopram or citalopram doses nearly saturated SERT in previous monkey studies which examined serotonin sensitivity of receptor radioligands. PET-measured cross-species differential effects of SSRI on cortical serotonin concentration may thus be related to SSRI dose. Future monkey studies using SSRI doses inducing clinically relevant SERT occupancy may further illuminate the delayed onset of SSRI therapeutic effects.

  16. In-vivo measurement of proton relaxation time (T1 and T2) in paediatric brain by MRI

    International Nuclear Information System (INIS)

    Masumura, Michio

    1986-01-01

    The clinical application of MRI led to the detailed imaging of the three-dimentional structure of the brain. Thus, significant information has been obtained with respect to the diagnosis of various diseases, rating severity, evaluation of curative effects, etc. On the other hand, the proportion of the comparative length of the relaxation time to the signal intensity of the images (especially the Spin-Echo image) was not necessarily linear. Consquently, the evaluation of severity was not easy to make. However, if we can obtain T 1 and T 2 precisely as the parameters costituting the images, it will be possible to overcome the above-mentioned difficulties. Further, the usefulness of MRI in activities such as determining the water metabolism of the brain is expected to increase even more. By means of VISTA-MR (0.15 Tesla, resistive magnet ; Picker International Co.) we measured the proton relaxation time (spin-lattice relaxation time (T 1 ) and spin-spin relaxation time (T 2 )) of various intracerebral lesions in paediatric cases. As the control group, 43 children, 4 adolescents and 6 adults were used. The T 1 and T 2 in the normal infantile cases prolonged significantly as compared with adult case. Thereafter, they become shortened by aging. In the age of two or three years, they reach the normal level of adult case. In the cases of degenerative disease, brain tumor, and cerebral contusion, the remarkable prolongation of both T 1 and T 2 , compared with normal value of the same age was observed. In the cases of brain atrophy and epilepsy, T 1 and T 2 were slightly short or within normal value of the same age. In the cases of intracerebral hemorrhage, T 1 was shortened. The in-vivo proton relaxation time obtained by MRI have various limits, but they can be a noninvasive and useful index in evaluation of severity or curative effects in various cerebral diseases. (author)

  17. Effects of intravenous glucose on Dopaminergic function in the human brain in vivo

    NARCIS (Netherlands)

    Haltia, Lauri T.; Rinne, Juha O.; Merisaari, Harri; Maguire, Ralph P.; Savontaus, Eriika; Helin, Semi; Nagren, Kjell; Kaasinen, Valtteri

    Dopamine is known to regulate food intake by modulating food reward via the mesolimbic circuitry of the brain. The objective of this study was to compare the effects of high energy input (i.v. glucose) on striatal and thalamic dopamine release in overweight and lean individuals. We hypothesized that

  18. Imaging separation of neuronal from vascular effects of cocaine on rat cortical brain in vivo

    International Nuclear Information System (INIS)

    Yuan, Z.; Du, C.; Luo, Z.; Volkow, N.D.; Pan, Y.

    2011-01-01

    MRI techniques to study brain function assume coupling between neuronal activity, metabolism and flow. However, recent evidence of physiological uncoupling between neuronal and cerebrovascular events highlights the need for methods to simultaneously measure these three properties. We report a multimodality optical approach that integrates dual-wavelength laser speckle imaging (measures changes in blood flow, blood volume and hemoglobin oxygenation), digital-frequency-ramping optical coherence tomography (images quantitative 3D vascular network) and Rhod2 fluorescence (images intracellular calcium for measure of neuronal activity) at high spatiotemporal resolutions (30 (micro)m, 10 Hz) and over a large field of view (3 x 5 mm 2 ). We apply it to assess cocaine's effects in rat cortical brain and show an immediate decrease 3.5 ± 0.9 min, phase (1) in the oxygen content of hemoglobin and the cerebral blood flow followed by an overshoot 7.1 ± 0.2 min, phase (2) lasting over 20 min whereas Ca 2+ increased immediately (peaked at t = 4.1 ± 0.4 min) and remained elevated. This enabled us to identify a delay (2.9 ± 0.5 min) between peak neuronal and vascular responses in phase 2. The ability of this multimodality optical approach for simultaneous imaging at high spatiotemporal resolutions permits us to distinguish the vascular versus cellular changes of the brain, thus complimenting other neuroimaging modalities for brain functional studies (e. g., PET, fMRI).

  19. In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.

    Science.gov (United States)

    Barrio, Jorge R; Small, Gary W; Wong, Koon-Pong; Huang, Sung-Cheng; Liu, Jie; Merrill, David A; Giza, Christopher C; Fitzsimmons, Robert P; Omalu, Bennet; Bailes, Julian; Kepe, Vladimir

    2015-04-21

    Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

  20. Imaging separation of neuronal from vascular effects of cocaine on rat cortical brain in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Z.; Du, C.; Yuan, Z.; Luo, Z.; Volkow, N.D.; Pan, Y.; Du, C.

    2010-09-08

    MRI techniques to study brain function assume coupling between neuronal activity, metabolism and flow. However, recent evidence of physiological uncoupling between neuronal and cerebrovascular events highlights the need for methods to simultaneously measure these three properties. We report a multimodality optical approach that integrates dual-wavelength laser speckle imaging (measures changes in blood flow, blood volume and hemoglobin oxygenation), digital-frequency-ramping optical coherence tomography (images quantitative 3D vascular network) and Rhod2 fluorescence (images intracellular calcium for measure of neuronal activity) at high spatiotemporal resolutions (30 {micro}m, 10 Hz) and over a large field of view (3 x 5 mm{sup 2}). We apply it to assess cocaine's effects in rat cortical brain and show an immediate decrease 3.5 {+-} 0.9 min, phase (1) in the oxygen content of hemoglobin and the cerebral blood flow followed by an overshoot 7.1 {+-} 0.2 min, phase (2) lasting over 20 min whereas Ca{sup 2+} increased immediately (peaked at t = 4.1 {+-} 0.4 min) and remained elevated. This enabled us to identify a delay (2.9 {+-} 0.5 min) between peak neuronal and vascular responses in phase 2. The ability of this multimodality optical approach for simultaneous imaging at high spatiotemporal resolutions permits us to distinguish the vascular versus cellular changes of the brain, thus complimenting other neuroimaging modalities for brain functional studies (e. g., PET, fMRI).

  1. Polymeric Nanoparticles for Nonviral Gene Therapy Extend Brain Tumor Survival in Vivo

    OpenAIRE

    Mangraviti, Antonella; Tzeng, Stephany Yi; Kozielski, Kristen Lynn; Wang, Yuan; Jin, Yike; Gullotti, David; Pedone, Mariangela; Buaron, Nitsa; Liu, Ann; Wilson, David R.; Hansen, Sarah K.; Rodriguez, Fausto J.; Gao, Guo-Dong; DiMeco, Francesco; Brem, Henry

    2015-01-01

    Biodegradable polymeric nanoparticles have the potential to be safer alternatives to viruses for gene delivery; however, their use has been limited by poor efficacy in vivo. In this work, we synthesize and characterize polymeric gene delivery nanoparticles and evaluate their efficacy for DNA delivery of herpes simplex virus type I thymidine kinase (HSVtk) combined with the prodrug ganciclovir (GCV) in a malignant glioma model. We investigated polymer structure for gene delivery in two rat gli...

  2. Nonviral gene therapy in vivo with PAM-RG4/apoptin as a potential brain tumor therapeutic

    Directory of Open Access Journals (Sweden)

    An S

    2013-02-01

    Full Text Available Songhie An,* Kihoon Nam,* Sunghyun Choi, Cheng Z Bai, Yan Lee, Jong-Sang ParkDepartment of Chemistry, Seoul National University, Seoul, Republic of Korea*These authors contributed equally to this workBackground: Glioma is still one of the most complicated forms of brain tumor to remove completely due to its location and the lack of an efficient means to specifically eliminate tumor cells. For these reasons, this study has examined the effectiveness of a nonviral gene therapy approach utilizing a tumor-selective killer gene on a brain tumor xenograft model.Methods and results: The therapeutic apoptin gene was recombined into the JDK plasmid and delivered into human brain tumor cells (U87MG by using a polyamidoamine dendrimer with an arginine surface (PAM-RG4. Studies in vitro showed that the PAM-RG4/apoptin plasmid polyplex exhibited a particularly high transfection activity of >40%. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL assay, 4´,6-Diamidino-2-phenylindole (DAPI TUNEL assay, DAPI staining, and caspase-3 activity assay verified that the tumor cells had undergone apoptosis induced by apoptin. For in vivo studies, the polyplex was injected into tumors, which were induced by injecting U87MG cells intradermally into nude mice. Based on hematoxylin and eosin staining, epidermal growth factor receptor immunohistochemistry results and tumor volume measurement results, tumor growth was effectively inhibited and no specific edema, irritation, or other harm to the skin was observed after polyplex injection. The in vivo expression of apoptin and the induction of apoptosis were verified by reverse-transcription polymerase chain reaction analysis, TUNEL assay, and DAPI staining.Conclusion: The PAM-RG4/apoptin gene polyplex is a strong candidate for brain tumor therapeutics because of the synergistic effect of the carrier's high transfection efficiency (35%–40% in glioma cells and the selective apoptosis-inducing activity of

  3. In-vivo brain blood flow imaging based on laser speckle contrast imaging and synchrotron radiation microangiography

    International Nuclear Information System (INIS)

    Miao, Peng; Feng, Shihan; Zhang, Qi; Lin, Xiaojie; Xie, Bohua; Liu, Chenwei; Yang, Guo-Yuan

    2014-01-01

    Abstract In-vivo imaging of blood flow in the cortex and sub-cortex is still a challenge in biological and pathological studies of cerebral vascular diseases. Laser speckle contrast imaging (LSCI) only provides cortex blood flow information. Traditional synchrotron radiation micro-angiography (SRA) provides sub-cortical vasculature information with high resolution. In this study, a bolus front-tracking method was developed to extract blood flow information based on SRA. Combining LSCI and SRA, arterial blood flow in the ipsilateral cortex and sub-cortex was monitored after experimental intracerebral hemorrhage of mice. At 72 h after injury, a significant blood flow increase was observed in the lenticulostriate artery along with blood flow decrease in cortical branches of the middle cerebral artery. This combined strategy provides a new approach for the investigation of brain vasculature and blood flow changes in preclinical studies. (paper)

  4. Proteolysis of His-Phe-Arg-Trp-Pro-Gly-Pro in the blood and brain of rats in vivo.

    Science.gov (United States)

    Shevchenko, K V; Nagaev, I Yu; Babakov, V N; Andreeva, L A; Shevchenko, V P; Radilov, A S; Myasoedov, N F

    2015-01-01

    The kinetics of the content of His-Phe-Arg-Trp-Pro-Gly-Pro (ACTH (6-9)PGP) and its hydrolysis products in the blood and brain of rats in the case of intranasal administration and intravenous injection of tritiated ACTH(6-9)PGP was studied. The parameters of bioavailability of ACTH(6-9)PGP administered intranasally were higher, indicating certain prospects in the intranasal application in clinical practice. We also found that the factor that determines ACTH(6-9)PGP proteolysis in experiments both in vivo and in vitro is aminopeptidases. The main products of ACTH(6-9)PGP during its metabolism in rats are short peptides and amino acids.

  5. Evidence of transcranial direct current stimulation-generated electric fields at subthalamic level in human brain in vivo.

    Science.gov (United States)

    Chhatbar, Pratik Y; Kautz, Steven A; Takacs, Istvan; Rowland, Nathan C; Revuelta, Gonzalo J; George, Mark S; Bikson, Marom; Feng, Wuwei

    2018-03-13

    Transcranial direct current stimulation (tDCS) is a promising brain modulation technique for several disease conditions. With this technique, some portion of the current penetrates through the scalp to the cortex and modulates cortical excitability, but a recent human cadaver study questions the amount. This insufficient intracerebral penetration of currents may partially explain the inconsistent and mixed results in tDCS studies to date. Experimental validation of a transcranial alternating current stimulation-generated electric field (EF) in vivo has been performed on the cortical (using electrocorticography, ECoG, electrodes), subcortical (using stereo electroencephalography, SEEG, electrodes) and deeper thalamic/subthalamic levels (using DBS electrodes). However, tDCS-generated EF measurements have never been attempted. We aimed to demonstrate that tDCS generates biologically relevant EF as deep as the subthalamic level in vivo. Patients with movement disorders who have implanted deep brain stimulation (DBS) electrodes serve as a natural experimental model for thalamic/subthalamic recordings of tDCS-generated EF. We measured voltage changes from DBS electrodes and body resistance from tDCS electrodes in three subjects while applying direct current to the scalp at 2 mA and 4 mA over two tDCS montages. Voltage changes at the level of deep nuclei changed proportionally with the level of applied current and varied with different tDCS montages. Our findings suggest that scalp-applied tDCS generates biologically relevant EF. Incorporation of these experimental results may improve finite element analysis (FEA)-based models. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. In vitro and ex vivo distribution of [3H]harmane, an endogenous beta-carboline, in rat brain.

    Science.gov (United States)

    Anderson, Neil J; Tyacke, Robin J; Husbands, Stephen M; Nutt, David J; Hudson, Alan L; Robinson, Emma S J

    2006-03-01

    The endogenous beta-carboline, harmane, has been shown to bind to monoamine oxidase A (MAO-A) and a separate, high affinity, non-MAO site. Research in our laboratory has shown that harmane is an active component of clonidine-displacing substance (CDS), the proposed endogenous ligand for imidazoline binding sites (IBS). In the present study we have investigated the distribution of [3H]harmane in rat brain, and related the binding profile to the distribution of the MAO-A selective ligand [3H]Ro41-1049 and the I2BS ligand [3H]2-BFI. The in vivo distribution of [3H]harmane following intravenous administration was also investigated. Receptor autoradiography revealed a highly significant correlation for the distribution of [3H]harmane and [3H]Ro41-1049, and a significant correlation for [3H]harmane and the I2BS ligand [3H]2-BFI. The in vivo distribution of [3H]harmane suggests that the ligand accumulates in the adrenal gland and throughout the brain with the primary route of excretion occurring via the duodenum. In conclusion, these studies have shown that [3H]harmane labels a population of binding sites that reflect the distribution of MAO-A. Further evidence for a non-MAO, IBS [3H]harmane population has not been shown but the high level of expression of the MAO-A site is likely to have masked the much smaller population of I2BS.

  7. Use of antimatter for the in vivo investigation of the brain: positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Syrota, A. [CEA, 75 - Paris (France)

    2002-07-01

    This series of slides presents 3 imaging methods used in medicine: - the single photon emission computed tomography (SPECT), the positron emission tomography (PET), and the functional magnetic resonance imaging (FMRI). The presentation begins with a brief historical description that highlights the narrow link between progress in imaging techniques and the technological development in radiation detection and computer sciences. Another aspect is the parallel and necessary development of isotopic tracers along with imaging techniques. The clinical applications of PET and FMRI concerning either normal brain functions such as calculus or consciousness or diseases affecting the central nervous system such as Parkinson's disease or schizophrenia (trough the study of the pathways of dopamine in the brain) are presented.

  8. In vivo brain anatomy of adult males with Fragile X syndrome: an MRI study.

    Science.gov (United States)

    Hallahan, Brian P; Craig, Michael C; Toal, Fiona; Daly, Eileen M; Moore, Caroline J; Ambikapathy, Anita; Robertson, Dene; Murphy, Kieran C; Murphy, Declan G M

    2011-01-01

    Fragile X Syndrome (FraX) is caused by the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, and is a leading cause of learning disability (mental retardation) worldwide. Relatively few studies, however, have examined the neuroanatomical abnormalities associated with FraX. Of those that are available many included mixed gender populations, combined FraX children and adults into one sample, and employed manual tracing techniques which measures bulk volume of particular regions. Hence, there is relatively little information on differences in grey and white matter content across whole brain. We employed magnetic resonance imaging to investigate brain anatomy in 17 adult males with FraX and 18 healthy controls that did not differ significantly in age. Data were analysed using stereology and VBM to compare (respectively) regional brain bulk volume, and localised grey/white matter content. Using stereology we found that FraX males had a significant increase in bulk volume bilaterally of the caudate nucleus and parietal lobes and of the right brainstem, but a significant decrease in volume of the left frontal lobe. Our complimentary VBM analysis revealed an increased volume of grey matter in fronto-striatal regions (including bilaterally in the caudate nucleus), and increased white matter in regions extending from the brainstem to the parahippocampal gyrus, and from the left cingulate cortex extending into the corpus callosum. People with FraX have regionally specific differences in brain anatomy from healthy controls with enlargement of the caudate nuclei that persists into adulthood. Copyright © 2010 Elsevier Inc. All rights reserved.

  9. In vivo brain anatomy of adult males with Fragile X syndrome: an MRI study.

    LENUS (Irish Health Repository)

    Hallahan, Brian P

    2011-01-01

    Fragile X Syndrome (FraX) is caused by the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, and is a leading cause of learning disability (mental retardation) worldwide. Relatively few studies, however, have examined the neuroanatomical abnormalities associated with FraX. Of those that are available many included mixed gender populations, combined FraX children and adults into one sample, and employed manual tracing techniques which measures bulk volume of particular regions. Hence, there is relatively little information on differences in grey and white matter content across whole brain. We employed magnetic resonance imaging to investigate brain anatomy in 17 adult males with FraX and 18 healthy controls that did not differ significantly in age. Data were analysed using stereology and VBM to compare (respectively) regional brain bulk volume, and localised grey\\/white matter content. Using stereology we found that FraX males had a significant increase in bulk volume bilaterally of the caudate nucleus and parietal lobes and of the right brainstem, but a significant decrease in volume of the left frontal lobe. Our complimentary VBM analysis revealed an increased volume of grey matter in fronto-striatal regions (including bilaterally in the caudate nucleus), and increased white matter in regions extending from the brainstem to the parahippocampal gyrus, and from the left cingulate cortex extending into the corpus callosum. People with FraX have regionally specific differences in brain anatomy from healthy controls with enlargement of the caudate nuclei that persists into adulthood.

  10. Monitoring mutations in people: an in vivo study of people accidentally or occupationally exposed to ionizing radiation

    International Nuclear Information System (INIS)

    Glickman, B.W.

    1996-01-01

    Recent developments in molecular biology and medicine now permit the monitoring of mutation in humans 'in vivo'. The most commonly used approach, and the main one reported in this paper, is the study of mutations at the hypoxanthine phosphoribosyl transferase (hprt) locus in peripheral T-lymphocytes. This paper deals with evidence from the radiological accident in Goiania, Brazil (where several hundred people were accidentally exposed to cesium-137), from a study of Soviet cosmonauts, and from monozygotic twins. The conclusions from Brazil are: mutation at hprt increases with age and is higher in smokers; in adults a linear dose response was found; no radiation-induced mutational fingerprint was found; children are particularly sensitive; the level of mutation dropped over several years (probably reflecting natural T-cell turnover). The conclusions from cosmonauts are: each cosmonaut had a significantly above-average level of mutation, but this may not be due to radiation at all; no 'fingerprint' was found, and there was no apparent dependence on dose. The study of twins showed a very strong correlation of mutant frequencies between one twin and the other, but this correlation decreased with age, presumably due to environmental effects. 1 tab., 2 figs

  11. Identifying lipidic emulsomes for improved oxcarbazepine brain targeting: In vitro and rat in vivo studies.

    Science.gov (United States)

    El-Zaafarany, Ghada M; Soliman, Mahmoud E; Mansour, Samar; Awad, Gehanne A S

    2016-04-30

    Lipid-based nanovectors offer effective carriers for brain delivery by improving drug potency and reducing off-target effects. Emulsomes are nano-triglyceride (TG) carriers formed of lipid cores supported by at least one phospholipid (PC) sheath. Due to their surface active properties, PC forms bilayers at the aqueous interface, thereby enabling encapsulated drug to benefit from better bioavailability and stability. Emulsomes of oxcarbazepine (OX) were prepared, aimed to offer nanocarriers for nasal delivery for brain targeting. Different TG cores (Compritol(®), tripalmitin, tristearin and triolein) and soya phosphatidylcholine in different amounts and ratios were used for emulsomal preparation. Particles were modulated to generate nanocarriers with suitable size, charge, encapsulation efficiency and prolonged release. Cytotoxicity and pharmacokinetic studies were also implemented. Nano-spherical OX-emulsomes with maximal encapsulation of 96.75% were generated. Stability studies showed changes within 30.6% and 11.2% in the size and EE% after 3 months. MTT assay proved a decrease in drug toxicity by its encapsulation in emulsomes. Incorporation of OX into emulsomes resulted in stable nanoformulations. Tailoring emulsomes properties by modulating the surface charge and particle size produced a stable system for the lipophilic drug with a prolonged release profile and mean residence time and proved direct nose-to-brain transport in rats. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. 13C NMR for the assessment of human brain glucose metabolism in vivo

    International Nuclear Information System (INIS)

    Beckman, N.; Seelig, J.; Turkalj, I.; Keller, U.

    1991-01-01

    Proton-decoupled 13 C NMR spectra of the human head were obtained during hyperglycemic glucose clamping using intravenous infusions of [1- 13 C]glucose in normal volunteers. In addition to 13 C signals of mobile lipids, a variety of new metabolite resonances could be resolved for the first time in the human brain. At an enrichment level of 20% [1- 13 C]glucose, the signals of α- and β-glucose at 92.7 and 96.6 ppm, respectively, could be detected in the human brain after only an infusion period of 15 minutes. The spatial localization of the different regions of interest was confirmed by 13 C NMR spectroscopic imaging with a time resolution of 9 minutes. Increasing the enrichment level to 99% [1- 13 C]glucose not only improved the time resolution but allowed the detection of metabolic breakdown products of [1- 13 C]glucose. The time course of 13 C label incorporation into the C 2 , C 3 , and C 4 resonances of glutamate/glutamine and into lactate could be recorded in the human brain. These results suggest the possibility of obtaining time-resolved, spatially selective, and chemically specific information on the human body

  13. Transplanted Adult Neural Stem Cells Express Sonic Hedgehog In Vivo and Suppress White Matter Neuroinflammation after Experimental Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Genevieve M. Sullivan

    2017-01-01

    Full Text Available Neural stem cells (NSCs delivered intraventricularly may be therapeutic for diffuse white matter pathology after traumatic brain injury (TBI. To test this concept, NSCs isolated from adult mouse subventricular zone (SVZ were transplanted into the lateral ventricle of adult mice at two weeks post-TBI followed by analysis at four weeks post-TBI. We examined sonic hedgehog (Shh signaling as a candidate mechanism by which transplanted NSCs may regulate neuroregeneration and/or neuroinflammation responses of endogenous cells. Mouse fluorescent reporter lines were generated to enable in vivo genetic labeling of cells actively transcribing Shh or Gli1 after transplantation and/or TBI. Gli1 transcription is an effective readout for canonical Shh signaling. In ShhCreERT2;R26tdTomato mice, Shh was primarily expressed in neurons and was not upregulated in reactive astrocytes or microglia after TBI. Corroborating results in Gli1CreERT2;R26tdTomato mice demonstrated that Shh signaling was not upregulated in the corpus callosum, even after TBI or NSC transplantation. Transplanted NSCs expressed Shh in vivo but did not increase Gli1 labeling of host SVZ cells. Importantly, NSC transplantation significantly reduced reactive astrogliosis and microglial/macrophage activation in the corpus callosum after TBI. Therefore, intraventricular NSC transplantation after TBI significantly attenuated neuroinflammation, but did not activate host Shh signaling via Gli1 transcription.

  14. Assessment of in vivo MR imaging compared to physical sections in vitro-A quantitative study of brain volumes using stereology

    DEFF Research Database (Denmark)

    Jelsing, Jacob; Rostrup, Egill; Markenroth, Karin

    2005-01-01

    The object of the present study was to compare stereological estimates of brain volumes obtained in vivo by magnetic resonance imaging (MRI) to corresponding volumes from physical sections in vitro. Brains of ten domestic pigs were imaged using a 3-T scanner. The volumes of different brain....... However, although intraobserver difference of MRI estimates was acceptable, the interobserver difference was not. A statistical highly significant difference of 11-41% was observed between observers for volume estimates of all compartments considered. The study demonstrates that quantitative MRI...

  15. In vivo sulfation of cholecystokinin octapeptide. Possible interactions of the two forms of cholecystokinin with dopamine in the brain

    International Nuclear Information System (INIS)

    Penke, B.; Kovacs, G.L.; Zsigo, J.; Kadar, T.; Szabo, G.; Kovacs, K.; Telegdy, G.

    1985-01-01

    In most laboratories CCK-8(s) has been found to be the biologically active form of CCK-8 in the CNS. The role of CCK-8(ns) has scarcely been investigated and is poorly understood. These results point to the equivalence of CCK-8(s) and CCK-8(ns) in the CNS in most biological tests. It is most likely that a brain receptor population exists which can bind both forms of CCK-8 and even CCK-4. Nevertheless, the CNS could contain binding sites which bind only CCK-8(s) as a ligand. The authors have found that an unidentified sulfotransferase of the brain can sulfate CCK-8(ns) and thereby provide a ligand for the special receptors of CCK-8(s). The authors have focused their investigations on the enzymic sulfation-desulfation processes of both CCK-8 and DA and have devised a hypothetical model for the possible interactions. Both CCK-8(ns) and DA could be sulfated in vivo, this enzymic reaction generally requiring active sulfate (PAPS). These two compounds could compete for the limited pool of PAPS, and thus CCK-8 and DA could mutually regulate their levels in the same cell by influencing one of the metabolic (DA) or synthetic (CCK-8(s)) pathways

  16. The blood-brain barrier is intact after levodopa-induced dyskinesias in parkinsonian primates--evidence from in vivo neuroimaging studies

    DEFF Research Database (Denmark)

    Astradsson, Arnar; Jenkins, Bruce G; Choi, Ji-Kyung

    2009-01-01

    It has been suggested, based on rodent studies, that levodopa (L-dopa) induced dyskinesia is associated with a disrupted blood-brain barrier (BBB). We have investigated BBB integrity with in vivo neuroimaging techniques in six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned primates...

  17. In vivo imaging of cerebral hemodynamics and tissue scattering in rat brain using a surgical microscope camera system

    Science.gov (United States)

    Nishidate, Izumi; Kanie, Takuya; Mustari, Afrina; Kawauchi, Satoko; Sato, Shunichi; Sato, Manabu; Kokubo, Yasuaki

    2018-02-01

    We investigated a rapid imaging method to monitor the spatial distribution of total hemoglobin concentration (CHbT), the tissue oxygen saturation (StO2), and the scattering power b in the expression of musp=a(lambda)^-b as the scattering parameters in cerebral cortex using a digital red-green-blue camera. In the method, Monte Carlo simulation (MCS) for light transport in brain tissue is used to specify a relation among the RGB-values and the concentration of oxygenated hemoglobin (CHbO), that of deoxygenated hemoglobin (CHbR), and the scattering power b. In the present study, we performed sequential recordings of RGB images of in vivo exposed brain of rats while changing the fraction of inspired oxygen (FiO2), using a surgical microscope camera system. The time courses of CHbO, CHbR, CHbT, and StO2 indicated the well-known physiological responses in cerebral cortex. On the other hand, a fast decrease in the scattering power b was observed immediately after the respiratory arrest, which is similar to the negative deflection of the extracellular DC potential so-called anoxic depolarization. It is said that the DC shift coincident with a rise in extracellular potassium and can evoke cell deformation generated by water movement between intracellular and extracellular compartments, and hence the light scattering by tissue. Therefore, the decrease in the scattering power b after the respiratory arrest is indicative of changes in light scattering by tissue. The results in this study indicate potential of the method to evaluate the pathophysiological conditions and loss of tissue viability in brain tissue.

  18. Regional variation of white matter development in the cat brain revealed by ex vivo diffusion MR tractography.

    Science.gov (United States)

    Dai, Guangping; Das, Avilash; Hayashi, Emiko; Chen, Qin; Takahashi, Emi

    2016-11-01

    Three-dimensional reconstruction of developing fiber pathways is essential to assessing the developmental course of fiber pathways in the whole brain. We applied diffusion spectrum imaging (DSI) tractography to five juvenile ex vivo cat brains at postnatal day (P) 35, when the degree of myelination varies across brain regions. We quantified diffusion properties (fractional anisotropy [FA] and apparent diffusion coefficient [ADC]) and other measurements (number, volume, and voxel count) on reconstructed pathways for projection (cortico-spinal and thalamo-cortical), corpus callosal, limbic (cingulum and fornix), and association (cortico-cortical) pathways, and characterized regional differences in maturation patterns by assessing diffusion properties. FA values were significantly higher in cortico-cortical pathways within the right hemisphere compared to those within the left hemisphere, while the other measurements for the cortico-cortical pathways within the hemisphere did not show asymmetry. ADC values were not asymmetric in both types of pathways. Interestingly, tract count and volume were significantly larger in the left thalamo-cortical pathways compared to the right thalamo-cortical pathways. The bilateral thalamo-cortical pathways showed high FA values compared to the other fiber pathways. On the other hand, ADC values did not show any differences across pathways studied. These results demonstrate that DSI tractography successfully depicted regional variations of white matter tracts during development when myelination is incomplete. Low FA and high ADC values in the cingulum bundle suggest that the cingulum bundle is less mature than the others at this developmental stage. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

  19. An in vivo study on brain microstructure in biological and chronological ageing

    DEFF Research Database (Denmark)

    Altmann-Schneider, Irmhild; de Craen, Anton J M; van den Berg-Huysmans, Annette A

    2015-01-01

    phenotype of familial longevity. Moreover, we aimed to describe cerebral ageing effects on MTI parameters in an elderly cohort. All subjects were included from the Leiden Longevity Study and underwent 3 Tesla MTI of the brain. In total, 183 offspring of nonagenarian siblings, who are enriched for familial...... factors of longevity, were contrasted with 163 environmentally and age-matched controls. No differences in cortical and subcortical gray matter and white matter MTI parameters were found between offspring and control subjects using histogram-based and voxel-wise analyses. Cortical gray matter and white...... matter MTI parameters decreased with increasing chronological age (all p

  20. An original emission tomograph for in vivo brain imaging of small animals

    International Nuclear Information System (INIS)

    Ochoa, A.V.; Ploux, L.; Mastrippolito, R.

    1996-01-01

    The principle of a new tomograph TOHR dedicated for small volume analysis with very high resolution is presented in this paper. We use uncorrelated multi-photons (X or gamma rays) radioisotopes and a large solid angle focusing collimator to make tomographic imaging without reconstruction algorithm. With this original device, detection efficiency and resolution are independent and submillimetric resolution can be achieved. A feasibility study shows that, made achieve the predicted performances of TOHR. We discuss its potential in rat brain tomography by simulating a realistic neuropharmacological experiment using a 1.4 mm resolution prototype of TOHR under development

  1. A Programmable High-Voltage Compliance Neural Stimulator for Deep Brain Stimulation in Vivo

    Directory of Open Access Journals (Sweden)

    Cihun-Siyong Alex Gong

    2015-05-01

    Full Text Available Deep brain stimulation (DBS is one of the most effective therapies for movement and other disorders. The DBS neurosurgical procedure involves the implantation of a DBS device and a battery-operated neurotransmitter, which delivers electrical impulses to treatment targets through implanted electrodes. The DBS modulates the neuronal activities in the brain nucleus for improving physiological responses as long as an electric discharge above the stimulation threshold can be achieved. In an effort to improve the performance of an implanted DBS device, the device size, implementation cost, and power efficiency are among the most important DBS device design aspects. This study aims to present preliminary research results of an efficient stimulator, with emphasis on conversion efficiency. The prototype stimulator features high-voltage compliance, implemented with only a standard semiconductor process, without the use of extra masks in the foundry through our proposed circuit structure. The results of animal experiments, including evaluation of evoked responses induced by thalamic electrical stimuli with our fabricated chip, were shown to demonstrate the proof of concept of our design.

  2. Normal variation and long-term reproducibility of image-selected in vivo brain MR spectroscopy

    International Nuclear Information System (INIS)

    Smith, M.A.; Porter, D.; Lowry, M.; Ayton, V.; Twelves, C.J.; Richards, M.A.; Garlick, P.; Maisey, M.N.

    1988-01-01

    MR spectroscopy of P-31 in the brain was performed with a 1.5-T MR imaging and spectroscopy system using ISIS with a 5-cm cube. A standardized spectral processing routine was adopted, and the ratios of peak areas were measured. Localized brain spectra were obtained from 17 healthy subjects, of whom ten had undergone repeated investigations after a delay of at least 1 month. The variation among healthy subjects, expressed as the mean +- standard deviation, and the long-term reproducibility, expressed as the coefficient of variation, were as follows: for peak areas phosphocreatine (PCr) Pi 2.46 +- 0.72, 21.3%, for PCr/PME, 1.97 +- 0.62, 16.8%, for PCr/PDE, 0.51 +- 0.07, 8.1%; for PCr/Υ-adenosine triphosphate (ATP), 1.13 + 0.15, 6.3%; for PCr/α-ATP, 1.09 +- 0.21, 10.3%, for PCr/β-ATP, 1.66 +- .027, 10.4%; and for pH, 7.00 +- 0.05, 0.8%

  3. In vivo proton magnetic resonance spectroscopy of intraventricular tumours of the brain

    International Nuclear Information System (INIS)

    Majos, Carles; Aguilera, Carles; Cos, Monica; Camins, Angels; Samitier, Alex; Castaner, Sara; Sanchez, Juan J.; Candiota, Ana P.; Delgado-Goni, Teresa; Mato, David; Acebes, Juan J.; Arus, Carles

    2009-01-01

    The aim of this study was to assess the usefulness of proton MR spectroscopy in the diagnosis of intraventricular tumours. Fifty-two intraventricular tumours pertaining to 16 different tumour types were derived from our database. All cases had single-voxel proton MR spectroscopy performed at TE at both 30 and 136 ms at 1.5 T. The Mann-Whitney U test was used to search for the most discriminative datapoints each tumour type. Characteristic trends were found for some groups: high Glx and Ala in meningiomas (p<0.001 and p<0.01, respectively), high mobile lipids in metastasis (p<0.001), high Cho in PNET (p<0.001), high mI+Gly in ependymoma (p<0.001), high NAC (p<0.01) in the absence of the normal brain parenchyma pattern in colloid cysts, and high mI/Gly and Ala in central neurocytoma. Proton MR spectroscopy provides additional metabolic information that could be useful in the diagnosis of intraventricular brain tumors. (orig.)

  4. In vivo proton magnetic resonance spectroscopy of intraventricular tumours of the brain

    Energy Technology Data Exchange (ETDEWEB)

    Majos, Carles; Aguilera, Carles [Hospital Universitari de Bellvitge, Institut de Diagnostic per la Imatge (IDI). Centre Bellvitge, L' Hospitalet de Llobregat, Barcelona (Spain); Biomateriales y Nanomedicina (CIBER-BBN), Centro de Investigacion Biomedica en Red en Bioingenieria, Cerdanyola del Valles (Spain); Cos, Monica; Camins, Angels; Samitier, Alex; Castaner, Sara; Sanchez, Juan J. [Hospital Universitari de Bellvitge, Institut de Diagnostic per la Imatge (IDI). Centre Bellvitge, L' Hospitalet de Llobregat, Barcelona (Spain); Candiota, Ana P.; Delgado-Goni, Teresa [Biomateriales y Nanomedicina (CIBER-BBN), Centro de Investigacion Biomedica en Red en Bioingenieria, Cerdanyola del Valles (Spain); Unitat de Bioquimica de Biociencies, Department de Bioquimica i Biologia Molecular, Cerdanyola del Valles (Spain); Mato, David [Hospital Universitari de Bellvitge, Department of Neurosurgery, L' Hospitalet de Llobregat, Barcelona (Spain); Acebes, Juan J. [Hospital Universitari de Bellvitge, Department of Neurosurgery, L' Hospitalet de Llobregat, Barcelona (Spain); Biomateriales y Nanomedicina (CIBER-BBN), Centro de Investigacion Biomedica en Red en Bioingenieria, Cerdanyola del Valles (Spain); Arus, Carles [Unitat de Bioquimica de Biociencies, Department de Bioquimica i Biologia Molecular, Cerdanyola del Valles (Spain); Biomateriales y Nanomedicina (CIBER-BBN), Centro de Investigacion Biomedica en Red en Bioingenieria, Cerdanyola del Valles (Spain)

    2009-08-15

    The aim of this study was to assess the usefulness of proton MR spectroscopy in the diagnosis of intraventricular tumours. Fifty-two intraventricular tumours pertaining to 16 different tumour types were derived from our database. All cases had single-voxel proton MR spectroscopy performed at TE at both 30 and 136 ms at 1.5 T. The Mann-Whitney U test was used to search for the most discriminative datapoints each tumour type. Characteristic trends were found for some groups: high Glx and Ala in meningiomas (p<0.001 and p<0.01, respectively), high mobile lipids in metastasis (p<0.001), high Cho in PNET (p<0.001), high mI+Gly in ependymoma (p<0.001), high NAC (p<0.01) in the absence of the normal brain parenchyma pattern in colloid cysts, and high mI/Gly and Ala in central neurocytoma. Proton MR spectroscopy provides additional metabolic information that could be useful in the diagnosis of intraventricular brain tumors. (orig.)

  5. Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo.

    Science.gov (United States)

    Mangraviti, Antonella; Tzeng, Stephany Yi; Kozielski, Kristen Lynn; Wang, Yuan; Jin, Yike; Gullotti, David; Pedone, Mariangela; Buaron, Nitsa; Liu, Ann; Wilson, David R; Hansen, Sarah K; Rodriguez, Fausto J; Gao, Guo-Dong; DiMeco, Francesco; Brem, Henry; Olivi, Alessandro; Tyler, Betty; Green, Jordan J

    2015-02-24

    Biodegradable polymeric nanoparticles have the potential to be safer alternatives to viruses for gene delivery; however, their use has been limited by poor efficacy in vivo. In this work, we synthesize and characterize polymeric gene delivery nanoparticles and evaluate their efficacy for DNA delivery of herpes simplex virus type I thymidine kinase (HSVtk) combined with the prodrug ganciclovir (GCV) in a malignant glioma model. We investigated polymer structure for gene delivery in two rat glioma cell lines, 9L and F98, to discover nanoparticle formulations more effective than the leading commercial reagent Lipofectamine 2000. The lead polymer structure, poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) end-modified with 1-(3-aminopropyl)-4-methylpiperazine, is a poly(β-amino ester) (PBAE) and formed nanoparticles with HSVtk DNA that were 138 ± 4 nm in size and 13 ± 1 mV in zeta potential. These nanoparticles containing HSVtk DNA showed 100% cancer cell killing in vitro in the two glioma cell lines when combined with GCV exposure, while control nanoparticles encoding GFP maintained robust cell viability. For in vivo evaluation, tumor-bearing rats were treated with PBAE/HSVtk infusion via convection-enhanced delivery (CED) in combination with systemic administration of GCV. These treated animals showed a significant benefit in survival (p = 0.0012 vs control). Moreover, following a single CED infusion, labeled PBAE nanoparticles spread completely throughout the tumor. This study highlights a nanomedicine approach that is highly promising for the treatment of malignant glioma.

  6. In vivo imaging of induction of heat-shock protein-70 gene expression with fluorescence reflectance imaging and intravital confocal microscopy following brain ischaemia in reporter mice.

    Science.gov (United States)

    de la Rosa, Xavier; Santalucía, Tomàs; Fortin, Pierre-Yves; Purroy, Jesús; Calvo, Maria; Salas-Perdomo, Angélica; Justicia, Carles; Couillaud, Franck; Planas, Anna M

    2013-02-01

    Stroke induces strong expression of the 72-kDa heat-shock protein (HSP-70) in the ischaemic brain, and neuronal expression of HSP-70 is associated with the ischaemic penumbra. The aim of this study was to image induction of Hsp-70 gene expression in vivo after brain ischaemia using reporter mice. A genomic DNA sequence of the Hspa1b promoter was used to generate an Hsp70-mPlum far-red fluorescence reporter vector. The construct was tested in cellular systems (NIH3T3 mouse fibroblast cell line) by transient transfection and examining mPlum and Hsp-70 induction under a challenge. After construct validation, mPlum transgenic mice were generated. Focal brain ischaemia was induced by transient intraluminal occlusion of the middle cerebral artery and the mice were imaged in vivo with fluorescence reflectance imaging (FRI) with an intact skull, and with confocal microscopy after opening a cranial window. Cells transfected with the Hsp70-mPlum construct showed mPlum fluorescence after stimulation. One day after induction of ischaemia, reporter mice showed a FRI signal located in the HSP-70-positive zone within the ipsilateral hemisphere, as validated by immunohistochemistry. Live confocal microscopy allowed brain tissue to be visualized at the cellular level. mPlum fluorescence was observed in vivo in the ipsilateral cortex 1 day after induction of ischaemia in neurons, where it is compatible with penumbra and neuronal viability, and in blood vessels in the core of the infarction. This study showed in vivo induction of Hsp-70 gene expression in ischaemic brain using reporter mice. The fluorescence signal showed in vivo the induction of Hsp-70 in penumbra neurons and in the vasculature within the ischaemic core.

  7. In vivo magnetic resonance diffusion measurement in the brain of patients with multiple sclerosis

    DEFF Research Database (Denmark)

    Larsson, H B; Thomsen, C; Frederiksen, J

    1992-01-01

    Measurement of water self-diffusion in the brain in 25 patients with multiple sclerosis was performed by magnetic resonance imaging. Quantitative diffusion measurements were obtained using single spin-echo pulse sequences with pulsed magnetic field gradients of different magnitude. Twenty......-two of these patients also underwent measurement of the transverse relaxation time (T2). Only one plaque was evaluated in each patient. Based on prior knowledge, 12 plaques were classified as being 3 mo or less in age, and 7 plaques were classified as being more than 3 mo old. In all 25 plaques, water self......-diffusion was found to be higher than in apparently normal white matter. Furthermore, water self-diffusion was found to be higher in acute plaques compared with chronic plaques. Finally, a slight tendency toward a relationship between the diffusion capability and T2 was found. We believe that an increased diffusion...

  8. Brain energy metabolism and dopaminergic function in Huntington's disease measured in vivo using positron emission tomography

    International Nuclear Information System (INIS)

    Leenders, K.L.; Frackowiak, R.S.; Quinn, N.; Marsden, C.D.

    1986-01-01

    A 48-year-old man with typical Huntington's disease was investigated with computed tomography (CT) and positron emission tomography. Regional cerebral blood flow, oxygen extraction, oxygen and glucose utilization, L-Dopa uptake, and dopamine (D2) receptor binding were measured using several positron-labelled tracers. CT showed slight atrophy of the head of caudate but no cortical atrophy, although distinct frontal lobe dysfunction was present on psychometric testing. Oxygen and glucose metabolism and cerebral blood flow were decreased in the striata and to a lesser extent in frontal cortex. Cerebral blood flow was in the low normal range throughout the remainder of the brain. A normal metabolic ratio was found in all regions, since the changes in glucose utilization paralleled those in oxygen consumption. The capacity of the striatum to store dopamine as assessed by L-[ 18 F]-fluorodopa uptake was normal, but dopamine (D2) receptor binding was decreased when compared to normal subjects

  9. In vivo regulation of the serotonin-2 receptor in rat brain

    International Nuclear Information System (INIS)

    Stockmeier, C.A.; Kellar, K.J.

    1986-01-01

    Serotonin-2 (5-HT-2) receptors in brain were measured using ( 3 H)ketanserin. The authors examined the effects of amitriptyline, an anti-depressant drug, of electroconvulsive shock (ECS) and of drug-induced alterations in presynaptic 5-HT function on ( 3 H)ketanserin binding to 5-HT-2 receptors in rat brain. The importance of intact 5-HT axons to the up-regulation of 5-HT-2 receptors by ECS was also investigated, and an attempt was made to relate the ECS-induced increase in this receptor to changes in 5-HT presynaptic mechanisms. Twelve days of ECS increased the number of 5-HT-2 receptors in frontal cortex. Neither the IC 50 nor the Hill coefficient of 5-HT in competing for ( 3 H)ketanserin binding sites was altered by ECS. Repeated injections of amitriptyline reduced the number of 5-HT-2 receptors in frontal cortex. Reserpine, administered daily for 12 days, caused a significant increase in 5-HT-2 receptors, but neither daily injections of p-chlorophenylalanine (PCPA) nor lesions of 5-HT axons with 5,7-dihydroxytryptamine (5,7-DHT) affected 5-HT-2 receptors. However, regulation of 5-HT-2 receptors by ECS was dependent on intact 5-HT axons since ECS could not increase the number of 5-HT-2 receptors in rats previously lesioned with 5,7-DHT. Repeated ECS, however, does not appear to affect either the high-affinity uptake of ( 3 H)5-HT or ( 3 H)imipramine binding, two presynaptic markers of 5-HT neuronal function. 5-HT-2 receptors appear to be under complex control. ECS or drug treatments such as reserpine or amitriptyline, which affect several monoamine neurotransmission systems including 5-HT, can alter 5-HT-2 receptors. 28 references, 1 figure, 7 tables

  10. In Vivo Tumour Mapping Using Electrocorticography Alterations During Awake Brain Surgery: A Pilot Study.

    Science.gov (United States)

    Boussen, Salah; Velly, Lionel; Benar, Christian; Metellus, Philippe; Bruder, Nicolas; Trébuchon, Agnès

    2016-09-01

    During awake brain surgery for tumour resection, in situ EEG recording (ECoG) is used to identify eloquent areas surrounding the tumour. We used the ECoG setup to record the electrical activity of cortical and subcortical tumours and then performed frequency and connectivity analyses in order to identify ECoG impairments and map tumours. We selected 16 patients with cortical (8) and subcortical (8) tumours undergoing awake brain surgery. For each patient, we computed the spectral content of tumoural and healthy areas in each frequency band. We computed connectivity of each electrode using connectivity markers (linear and non-linear correlations, phase-locking and coherence). We performed comparisons between healthy and tumour electrodes. The ECoG alterations were used to implement automated classification of the electrodes using clustering or neural network algorithms. ECoG alterations were used to image cortical tumours.Cortical tumours were found to profoundly alter all frequency contents (normalized and absolute power), with an increase in the δ activity and a decreases for the other bands (P < 0.05). Cortical tumour electrodes showed high level of connectivity compared to surrounding electrodes (all markers, P < 0.05). For subcortical tumours, a relative decrease in the γ1 band and in the alpha band in absolute amplitude (P < 0.05) were the only abnormalities. The neural network algorithm classification had a good performance: 93.6 % of the electrodes were classified adequately on a test subject. We found significant spectral and connectivity ECoG changes for cortical tumours, which allowed tumour recognition. Artificial neural algorithm pattern recognition seems promising for electrode classification in awake tumour surgery.

  11. Occupational Clusters.

    Science.gov (United States)

    Pottawattamie County School System, Council Bluffs, IA.

    The 15 occupational clusters (transportation, fine arts and humanities, communications and media, personal service occupations, construction, hospitality and recreation, health occupations, marine science occupations, consumer and homemaking-related occupations, agribusiness and natural resources, environment, public service, business and office…

  12. Mapping Magnetic Susceptibility Anisotropies of White Matter in vivo in the Human Brain at 7 Tesla

    Science.gov (United States)

    Li, Xu; Vikram, Deepti S; Lim, Issel Anne L; Jones, Craig K; Farrell, Jonathan A.D.; van Zijl, Peter C. M.

    2012-01-01

    High-resolution magnetic resonance phase- or frequency- shift images acquired at high field show contrast related to magnetic susceptibility differences between tissues. Such contrast varies with the orientation of the organ in the field, but the development of quantitative susceptibility mapping (QSM) has made it possible to reproducibly image the intrinsic tissue susceptibility contrast. However, recent studies indicate that magnetic susceptibility is anisotropic in brain white matter and, as such, needs to be described by a symmetric second-rank tensor (χ¯¯). To fully determine the elements of this tensor, it would be necessary to acquire frequency data at six or more orientations. Assuming cylindrical symmetry of the susceptibility tensor in myelinated white matter fibers, we propose a simplified method to reconstruct the susceptibility tensor in terms of a mean magnetic susceptibility, MMS = (χ∥ + 2χ⊥)/3 and a magnetic susceptibility anisotropy, MSA = χ∥ − χ⊥, where χ∥ and χ⊥ are susceptibility parallel and perpendicular to the white matter fiber direction, respectively. Computer simulations show that with a practical head rotation angle of around 20°–30°, four head orientations suffice to reproducibly reconstruct the tensor with good accuracy. We tested this approach on whole brain 1×1×1 mm3 frequency data acquired from five healthy subjects at 7 T. The frequency information from phase images collected at four head orientations was combined with the fiber direction information extracted from diffusion tensor imaging (DTI) to map the white matter susceptibility tensor. The MMS and MSA were quantified for regions in several large white matter fiber structures, including the corona radiata, posterior thalamic radiation and corpus callosum. MMS ranged from −0.037 to −0.053 ppm (referenced to CSF being about zero). MSA values could be quantified without the need for a reference and ranged between 0.004 and 0.029 ppm, in line with

  13. Identifying endogenous neural stem cells in the adult brain in vitro and in vivo: novel approaches.

    Science.gov (United States)

    Rueger, Maria Adele; Androutsellis-Theotokis, Andreas

    2013-01-01

    In the 1960s, Joseph Altman reported that the adult mammalian brain is capable of generating new neurons. Today it is understood that some of these neurons are derived from uncommitted cells in the subventricular zone lining the lateral ventricles, and the dentate gyrus of the hippocampus. The first area generates new neuroblasts which migrate to the olfactory bulb, whereas hippocampal neurogenesis seems to play roles in particular types of learning and memory. A part of these uncommitted (immature) cells is able to divide and their progeny can generate all three major cell types of the nervous system: neurons, astrocytes, and oligodendrocytes; these properties define such cells as neural stem cells. Although the roles of these cells are not yet clear, it is accepted that they affect functions including olfaction and learning/memory. Experiments with insults to the central nervous system also show that neural stem cells are quickly mobilized due to injury and in various disorders by proliferating, and migrating to injury sites. This suggests a role of endogenous neural stem cells in disease. New pools of stem cells are being discovered, suggesting an even more important role for these cells. To understand these cells and to coax them to contribute to tissue repair it would be very useful to be able to image them in the living organism. Here we discuss advances in imaging approaches as well as new concepts that emerge from stem cell biology with emphasis on the interface between imaging and stem cells.

  14. In vivo effect of sex steroids on uptake of 3H-leucine by female mouse brain

    International Nuclear Information System (INIS)

    Seiki, Kanji; Haruki, Yasuo; Imanishi, Yoshio

    1978-01-01

    In vivo effects of the sex steroids estrogen and progesterone on 3 H-leucine uptake by the brain of mature ovariectomized mice were examined. Animals were divided into three groups: group 1, consisting of control animals treated with sesame oil, group 2, animals treated with estrogen, and group 3, animals first treated with estrogen and then with progesterone. Each group was given a single i.p. injection of 3 H-leucine 2 hr after the last hormonal treatment, and sacrificed 2 hr later. Intensity of the uptake of radiolabeled leucine was measured by counting the number of reduced silver grains over cells in various brain regions using an autoradiographic technique. Group 1 showed a relatively high uptake in the supraoptic nucleus, paraventricular nucleus (PV) and ventromedial nucleus (VM) when compared with that in the remaining hypothalamic nuclei examined. Group 2 showed a significant enhancement of the uptake in all hypothalamic regions except the preoptic periventricular nucleus (PPV) when compared with that in group 1. Group 3 showed enhancement of the uptake in all hypothalamic nuclei when compared with that in group 1. However, only the PV, PPV, VM and periventricular arcuate nucleus revealed a significantly higher uptake than the respective nuclei in group 2. The remaining nuclei showed no change in uptake. Uptake by cells in the ependymal cells and cerebral cortex remained unchanged after hormonal treatment. The present results suggest that in female mice estrogen and estrogen plus progesterone stimulate protein synthesis in most of the hypothalamic nuclei and that the progesterone effect on protein synthesis is greatly influenced by estrogen-priming. (auth.)

  15. On the relationship between the two branches of the kynurenine pathway in the rat brain in vivo.

    Science.gov (United States)

    Amori, Laura; Guidetti, Paolo; Pellicciari, Roberto; Kajii, Yasushi; Schwarcz, Robert

    2009-04-01

    In the mammalian brain, kynurenine aminotransferase II (KAT II) and kynurenine 3-monooxygenase (KMO), key enzymes of the kynurenine pathway (KP) of tryptophan degradation, form the neuroactive metabolites kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK), respectively. Although physically segregated, both enzymes use the pivotal KP metabolite l-kynurenine as a substrate. We studied the functional consequences of this cellular compartmentalization in vivo using two specific tools, the KAT II inhibitor BFF 122 and the KMO inhibitor UPF 648. The acute effects of selective KAT II or KMO inhibition were studied using a radiotracing method in which the de novo synthesis of KYNA, and of 3-HK and its downstream metabolite quinolinic acid (QUIN), is monitored following an intrastriatal injection of (3)H-kynurenine. In naïve rats, intrastriatal BFF 122 decreased newly formed KYNA by 66%, without influencing 3-HK or QUIN production. Conversely, UPF 648 reduced 3-HK synthesis (by 64%) without affecting KYNA formation. Similar, selective effects of KAT II and KMO inhibition were observed when the inhibitors were applied acutely together with the excitotoxin QUIN, which impairs local KP metabolism. Somewhat different effects of KMO (but not KAT II) inhibition were obtained in rats that had received an intrastriatal QUIN injection 7 days earlier. In these neuron-depleted striata, UPF 648 not only decreased both 3-HK and QUIN production (by 77% and 66%, respectively) but also moderately raised KYNA synthesis (by 27%). These results indicate a remarkable functional segregation of the two pathway branches in the brain, boding well for the development of selective KAT II or KMO inhibitors for cognitive enhancement and neuroprotection, respectively.

  16. Live cell imaging techniques to study T cell trafficking across the blood-brain barrier in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Coisne Caroline

    2013-01-01

    Full Text Available Abstract Background The central nervous system (CNS is an immunologically privileged site to which access for circulating immune cells is tightly controlled by the endothelial blood–brain barrier (BBB located in CNS microvessels. Under physiological conditions immune cell migration across the BBB is low. However, in neuroinflammatory diseases such as multiple sclerosis, many immune cells can cross the BBB and cause neurological symptoms. Extravasation of circulating immune cells is a multi-step process that is regulated by the sequential interaction of different adhesion and signaling molecules on the immune cells and on the endothelium. The specialized barrier characteristics of the BBB, therefore, imply the existence of unique mechanisms for immune cell migration across the BBB. Methods and design An in vitro mouse BBB model maintaining physiological barrier characteristics in a flow chamber and combined with high magnification live cell imaging, has been established. This model enables the molecular mechanisms involved in the multi-step extravasation of T cells across the in vitro BBB, to be defined with high-throughput analyses. Subsequently these mechanisms have been verified in vivo using a limited number of experimental animals and a spinal cord window surgical technique. The window enables live observation of the dynamic interaction between T cells and spinal cord microvessels under physiological and pathological conditions using real time epifluorescence intravital imaging. These in vitro and in vivo live cell imaging methods have shown that the BBB endothelium possesses unique and specialized mechanisms involved in the multi-step T cell migration across this endothelial barrier under physiological flow. The initial T cell interaction with the endothelium is either mediated by T cell capture or by T cell rolling. Arrest follows, and then T cells polarize and especially CD4+ T cells crawl over long distances against the direction of

  17. Quantitative imaging of brain energy metabolisms and neuroenergetics using in vivo X-nuclear 2H, 17O and 31P MRS at ultra-high field.

    Science.gov (United States)

    Zhu, Xiao-Hong; Lu, Ming; Chen, Wei

    2018-07-01

    Brain energy metabolism relies predominantly on glucose and oxygen utilization to generate biochemical energy in the form of adenosine triphosphate (ATP). ATP is essential for maintaining basal electrophysiological activities in a resting brain and supporting evoked neuronal activity under an activated state. Studying complex neuroenergetic processes in the brain requires sophisticated neuroimaging techniques enabling noninvasive and quantitative assessment of cerebral energy metabolisms and quantification of metabolic rates. Recent state-of-the-art in vivo X-nuclear MRS techniques, including 2 H, 17 O and 31 P MRS have shown promise, especially at ultra-high fields, in the quest for understanding neuroenergetics and brain function using preclinical models and in human subjects under healthy and diseased conditions. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. In vivo EPR pharmacokinetic evaluation of the redox status and the blood brain barrier permeability in the SOD1G93A ALS rat model.

    Science.gov (United States)

    Stamenković, Stefan; Pavićević, Aleksandra; Mojović, Miloš; Popović-Bijelić, Ana; Selaković, Vesna; Andjus, Pavle; Bačić, Goran

    2017-07-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting the motor pathways of the central nervous system. Although a number of pathophysiological mechanisms have been described in the disease, post mortem and animal model studies indicate blood-brain barrier (BBB) disruption and elevated production of reactive oxygen species as major contributors to disease pathology. In this study, the BBB permeability and the brain tissue redox status of the SOD1 G93A ALS rat model in the presymptomatic (preALS) and symptomatic (ALS) stages of the disease were investigated by in vivo EPR spectroscopy using three aminoxyl radicals with different cell membrane and BBB permeabilities, Tempol, 3-carbamoyl proxyl (3CP), and 3-carboxy proxyl (3CxP). Additionally, the redox status of the two brain regions previously implicated in disease pathology, brainstem and hippocampus, was investigated by spectrophotometric biochemical assays. The EPR results indicated that among the three spin probes, 3CP is the most suitable for reporting the intracellular redox status changes, as Tempol was reduced in vivo within minutes (t 1/2 =2.0±0.5min), thus preventing reliable kinetic modeling, whereas 3CxP reduction kinetics gave divergent conclusions, most probably due to its membrane impermeability. It was observed that the reduction kinetics of 3CP in vivo, in the head of preALS and ALS SOD1 G93A rats was altered compared to the controls. Pharmacokinetic modeling of 3CP reduction in vivo, revealed elevated tissue distribution and tissue reduction rate constants indicating an altered brain tissue redox status, and possibly BBB disruption in these animals. The preALS and ALS brain tissue homogenates also showed increased nitrilation, superoxide production, lipid peroxidation and manganese superoxide dismutase activity, and a decreased copper-zinc superoxide dismutase activity. The present study highlights in vivo EPR spectroscopy as a reliable tool for the investigation of

  19. Transcranial direct current stimulation transiently increases the blood-brain barrier solute permeability in vivo

    Science.gov (United States)

    Shin, Da Wi; Khadka, Niranjan; Fan, Jie; Bikson, Marom; Fu, Bingmei M.

    2016-03-01

    Transcranial Direct Current Stimulation (tDCS) is a non-invasive electrical stimulation technique investigated for a broad range of medical and performance indications. Whereas prior studies have focused exclusively on direct neuron polarization, our hypothesis is that tDCS directly modulates endothelial cells leading to transient changes in blood-brain-barrier (BBB) permeability (P) that are highly meaningful for neuronal activity. For this, we developed state-of-the-art imaging and animal models to quantify P to various sized solutes after tDCS treatment. tDCS was administered using a constant current stimulator to deliver a 1mA current to the right frontal cortex of rat (approximately 2 mm posterior to bregma and 2 mm right to sagittal suture) to obtain similar physiological outcome as that in the human tDCS application studies. Sodium fluorescein (MW=376), or FITC-dextrans (20K and 70K), in 1% BSA mammalian Ringer was injected into the rat (SD, 250-300g) cerebral circulation via the ipsilateral carotid artery by a syringe pump at a constant rate of ~3 ml/min. To determine P, multiphoton microscopy with 800-850 nm wavelength laser was applied to take the images from the region of interest (ROI) with proper microvessels, which are 100-200 micron below the pia mater. It shows that the relative increase in P is about 8-fold for small solute, sodium fluorescein, ~35-fold for both intermediate sized (Dex-20k) and large (Dex-70k) solutes, 10 min after 20 min tDCS pretreatment. All of the increased permeability returns to the control after 20 min post treatment. The results confirmed our hypothesis.

  20. Effects of intravenous glucose on dopaminergic function in the human brain in vivo.

    Science.gov (United States)

    Haltia, Lauri T; Rinne, Juha O; Merisaari, Harri; Maguire, Ralph P; Savontaus, Eriika; Helin, Semi; Någren, Kjell; Kaasinen, Valtteri

    2007-09-01

    Dopamine is known to regulate food intake by modulating food reward via the mesolimbic circuitry of the brain. The objective of this study was to compare the effects of high energy input (i.v. glucose) on striatal and thalamic dopamine release in overweight and lean individuals. We hypothesized that glucose would induce dopamine release and positive ratings (e.g., satiety) in Behavioral Analog Scales, particularly in food-deprived lean subjects. [(11)C]raclopride PET was performed for 12 lean (mean BMI = 22 kg/m(2)) and 12 overweight (mean BMI = 33 kg/m(2)) healthy subjects. Each subject was imaged twice in a blinded counter-balanced setting, after 300 mg/kg i.v. glucose and after i.v. placebo. Dopamine D2 receptor binding potentials (BPs) were estimated. The voxel-based analysis of the baseline scans indicated lower striatal BPs in the overweight group and a negative correlation between BMIs and BPs. Intravenous glucose did not have a significant effect on BPs in overweight or lean subjects (male and female groups combined). However, BP changes were opposite in the two gender groups. In male subjects, significant BP reductions after glucose were seen in the right and left caudate nucleus, left putamen, and right thalamus. In female subjects, increases in BP secondary to glucose were seen in the right caudate nucleus and right and left putamen. The sexually dimorphic effect of glucose was seen in both overweight and lean subjects. Although gender differences were not among the a priori hypotheses of the present study and, therefore, they must be considered to be preliminary findings, we postulate that this observation is a reflection of an interaction between glucose, sex steroids (estrogen), leptin, and dopamine.

  1. Responses of the Human Brain to Mild Dehydration and Rehydration Explored In Vivo by 1H-MR Imaging and Spectroscopy.

    Science.gov (United States)

    Biller, A; Reuter, M; Patenaude, B; Homola, G A; Breuer, F; Bendszus, M; Bartsch, A J

    2015-12-01

    As yet, there are no in vivo data on tissue water changes and associated morphometric changes involved in the osmo-adaptation of normal brains. Our aim was to evaluate osmoadaptive responses of the healthy human brain to osmotic challenges of de- and rehydration by serial measurements of brain volume, tissue fluid, and metabolites. Serial T1-weighted and (1)H-MR spectroscopy data were acquired in 15 healthy individuals at normohydration, on 12 hours of dehydration, and during 1 hour of oral rehydration. Osmotic challenges were monitored by serum measures, including osmolality and hematocrit. MR imaging data were analyzed by using FreeSurfer and LCModel. On dehydration, serum osmolality increased by 0.67% and brain tissue fluid decreased by 1.63%, on average. MR imaging morphometry demonstrated corresponding decreases of cortical thickness and volumes of the whole brain, cortex, white matter, and hypothalamus/thalamus. These changes reversed during rehydration. Continuous fluid ingestion of 1 L of water for 1 hour within the scanner lowered serum osmolality by 0.96% and increased brain tissue fluid by 0.43%, on average. Concomitantly, cortical thickness and volumes of the whole brain, cortex, white matter, and hypothalamus/thalamus increased. Changes in brain tissue fluid were related to volume changes of the whole brain, the white matter, and hypothalamus/thalamus. Only volume changes of the hypothalamus/thalamus significantly correlated with serum osmolality. This is the first study simultaneously evaluating changes in brain tissue fluid, metabolites, volume, and cortical thickness. Our results reflect cellular volume regulatory mechanisms at a macroscopic level and emphasize that it is essential to control for hydration levels in studies on brain morphometry and metabolism in order to avoid confounding the findings. © 2015 by American Journal of Neuroradiology.

  2. Kinetic analysis of transport and opioid receptor binding of ( sup 3 H)(-)-cyclofoxy in rat brain in vivo: Implications for human studies

    Energy Technology Data Exchange (ETDEWEB)

    Sawada, Y.; Kawai, R.; McManaway, M.; Otsuki, H.; Rice, K.C.; Patlak, C.S.; Blasberg, R.G. (National Institutes of Health, Bethesda, MD (USA))

    1991-03-01

    (3H)Cyclofoxy (CF: 17-cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta-fluoromorp hinan) is an opioid antagonist with affinity to both mu and kappa subtypes that was synthesized for quantitative evaluation of opioid receptor binding in vivo. Two sets of experiments in rats were analyzed. The first involved determining the metabolite-corrected blood concentration and tissue distribution of CF in brain 1 to 60 min after i.v. bolus injection. The second involved measuring brain washout for 15 to 120 s following intracarotid artery injection of CF. A physiologically based model and a classical compartmental pharmacokinetic model were compared. The models included different assumptions for transport across the blood-brain barrier (BBB); estimates of nonspecific tissue binding and specific binding to a single opiate receptor site were found to be essentially the same with both models. The nonspecific binding equilibrium constant varied modestly in different brain structures (Keq = 3-9), whereas the binding potential (BP) varied over a much broader range (BP = 0.6-32). In vivo estimates of the opioid receptor dissociation constant were similar for different brain structures (KD = 2.1-5.2 nM), whereas the apparent receptor density (Bmax) varied between 1 (cerebellum) and 78 (thalamus) pmol/g of brain. The receptor dissociation rate constants in cerebrum (k4 = 0.08-0.16 min-1; koff = 0.16-0.23 min-1) and brain vascular permeability (PS = 1.3-3.4 ml/min/g) are sufficiently high to achieve equilibrium conditions within a reasonable period of time. Graphical analysis of the data is inappropriate due to the high tissue-loss rate constant for CF in brain. From these findings, CF should be a very useful opioid receptor ligand for the estimation of the receptor binding parameters in human subjects using (18F)CF and positron emission tomography.

  3. Kinetic analysis of transport and opioid receptor binding of [3H](-)-cyclofoxy in rat brain in vivo: Implications for human studies

    International Nuclear Information System (INIS)

    Sawada, Y.; Kawai, R.; McManaway, M.; Otsuki, H.; Rice, K.C.; Patlak, C.S.; Blasberg, R.G.

    1991-01-01

    [3H]Cyclofoxy (CF: 17-cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta-fluoromorp hinan) is an opioid antagonist with affinity to both mu and kappa subtypes that was synthesized for quantitative evaluation of opioid receptor binding in vivo. Two sets of experiments in rats were analyzed. The first involved determining the metabolite-corrected blood concentration and tissue distribution of CF in brain 1 to 60 min after i.v. bolus injection. The second involved measuring brain washout for 15 to 120 s following intracarotid artery injection of CF. A physiologically based model and a classical compartmental pharmacokinetic model were compared. The models included different assumptions for transport across the blood-brain barrier (BBB); estimates of nonspecific tissue binding and specific binding to a single opiate receptor site were found to be essentially the same with both models. The nonspecific binding equilibrium constant varied modestly in different brain structures (Keq = 3-9), whereas the binding potential (BP) varied over a much broader range (BP = 0.6-32). In vivo estimates of the opioid receptor dissociation constant were similar for different brain structures (KD = 2.1-5.2 nM), whereas the apparent receptor density (Bmax) varied between 1 (cerebellum) and 78 (thalamus) pmol/g of brain. The receptor dissociation rate constants in cerebrum (k4 = 0.08-0.16 min-1; koff = 0.16-0.23 min-1) and brain vascular permeability (PS = 1.3-3.4 ml/min/g) are sufficiently high to achieve equilibrium conditions within a reasonable period of time. Graphical analysis of the data is inappropriate due to the high tissue-loss rate constant for CF in brain. From these findings, CF should be a very useful opioid receptor ligand for the estimation of the receptor binding parameters in human subjects using [18F]CF and positron emission tomography

  4. Neurokinin-3 Receptor Binding in Guinea Pig, Monkey, and Human Brain: In Vitro and in Vivo Imaging Using the Novel Radioligand, [18F]Lu AF10628.

    Science.gov (United States)

    Varnäs, Katarina; Finnema, Sjoerd J; Stepanov, Vladimir; Takano, Akihiro; Tóth, Miklós; Svedberg, Marie; Møller Nielsen, Søren; Khanzhin, Nikolay A; Juhl, Karsten; Bang-Andersen, Benny; Halldin, Christer; Farde, Lars

    2016-08-01

    Previous autoradiography studies have suggested a marked interspecies variation in the neuroanatomical localization and expression levels of the neurokinin 3 receptor, with high density in the brain of rat, gerbil, and guinea pig, but at the time offered no conclusive evidence for its presence in the human brain. Hitherto available radioligands have displayed low affinity for the human neurokinin 3 receptor relative to the rodent homologue and may thus not be optimal for cross-species analyses of the expression of this protein. A novel neurokinin 3 receptor radioligand, [(18)F]Lu AF10628 ((S)-N-(cyclobutyl(3-fluorophenyl)methyl)-8-fluoro-2-((3-[(18)F]-fluoropropyl)amino)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide), was synthesized and used for autoradiography studies in cryosections from guinea pig, monkey, and human brain as well as for positron emission tomography studies in guinea pig and monkey. The results confirmed previous observations of interspecies variation in the neurokinin 3 receptor brain localization with more extensive distribution in guinea pig than in primate brain. In the human brain, specific binding to the neurokinin 3 receptor was highest in the amygdala and in the hypothalamus and very low in other regions examined. Positron emission tomography imaging showed a pattern consistent with that observed using autoradiography. The radioactivity was, however, found to accumulate in skull bone, which limits the use of this radioligand for in vivo quantification of neurokinin 3 receptor binding. Species differences in the brain distribution of neurokinin 3 receptors should be considered when using animal models for predicting human neurokinin 3 receptor pharmacology. For positron emission tomography imaging of brain neurokinin 3 receptors, additional work is required to develop a radioligand with more favorable in vivo properties. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  5. Two-photon microscopy imaging of thy1GFP-M transgenic mice: a novel animal model to investigate brain dendritic cell subsets in vivo.

    Directory of Open Access Journals (Sweden)

    Claudia Laperchia

    Full Text Available Transgenic mice expressing fluorescent proteins in specific cell populations are widely used for in vivo brain studies with two-photon fluorescence (TPF microscopy. Mice of the thy1GFP-M line have been engineered for selective expression of green fluorescent protein (GFP in neuronal populations. Here, we report that TPF microscopy reveals, at the brain surface of these mice, also motile non-neuronal GFP+ cells. We have analyzed the behavior of these cells in vivo and characterized in brain sections their immunophenotype.With TPF imaging, motile GFP+ cells were found in the meninges, subarachnoid space and upper cortical layers. The striking feature of these cells was their ability to move across the brain parenchyma, exhibiting evident shape changes during their scanning-like motion. In brain sections, GFP+ cells were immunonegative to antigens recognizing motile cells such as migratory neuroblasts, neuronal and glial precursors, mast cells, and fibroblasts. GFP+ non-neuronal cells exhibited instead the characteristic features and immunophenotype (CD11c and major histocompatibility complex molecule class II immunopositivity of dendritic cells (DCs, and were immunonegative to the microglial marker Iba-1. GFP+ cells were also identified in lymph nodes and blood of thy1GFP-M mice, supporting their identity as DCs. Thus, TPF microscopy has here allowed the visualization for the first time of the motile behavior of brain DCs in situ. The results indicate that the thy1GFP-M mouse line provides a novel animal model for the study of subsets of these professional antigen-presenting cells in the brain. Information on brain DCs is still very limited and imaging in thy1GFP-M mice has a great potential for analyses of DC-neuron interaction in normal and pathological conditions.

  6. Whole-brain in-vivo measurements of the axonal g-ratio in a group of 37 healthy volunteers

    Directory of Open Access Journals (Sweden)

    Siawoosh eMohammadi

    2015-11-01

    Full Text Available The g-ratio, quantifying the ratio between the inner and outer diameters of a fiber, is an important microstructural characteristic of fiber pathways and is functionally related to conduction velocity. We introduce a novel method for estimating the MR g-ratio non-invasively across the whole brain using high-fidelity magnetization transfer (MT imaging and single-shell diffusion MRI. These methods enabled us to map the MR g-ratio in vivo across the brain’s prominent fiber pathways in a group of 37 healthy volunteers and to estimate the inter-subject variability. Effective correction of susceptibility-related distortion artifacts was essential before combining the MT and diffusion data, in order to reduce partial volume and edge artifacts. The MR g-ratio is in good qualitative agreement with histological findings despite the different resolution and spatial coverage of MRI and histology. The MR g-ratio holds promise as an important non-invasive biomarker due to its microstructural and functional relevance in neurodegeneration.

  7. In vivo binding in rat brain and radiopharmaceutical preparation of radioiodinated HEAT, an alpha-1 adrenoceptor ligand

    International Nuclear Information System (INIS)

    Couch, M.W.; Greer, D.M.; Thonoor, C.M.; Williams, C.M.

    1988-01-01

    In vivo binding of [ 125 I]-2-[beta-(3-iodo-4-hydroxyphenyl)ethylaminomethyl tetralone) ([ 125 I]HEAT) to alpha-1 adrenoceptors in the rat brain was determined over 4 hr. Uptake in the thalamus and frontal cortex was approximately 0.1% injected dose per gram tissue. Thalamus/cerebellum ratios of 10:1 and frontal cortex/cerebellum ratios of 5:1 were found at 4 hr. Pretreatment with prazosin, an alpha-1 antagonist, completely inhibited the accumulation of [ 125 I]HEAT in thalamus and frontal cortex; yet uptake of radioactivity was not significantly affected by antagonists and agonists for other receptors classes (propranolol, beta-1; apomorphine, D-1; spiperone, D-2). Binding of [ 125 I]HEAT is saturable. At 4 hr, [ 125 I]HEAT or [ 123 I]HEAT was shown to be the only radioactive material in rat thalamus and frontal cortex. Iodine-123 HEAT and [ 125 I]HEAT were synthesized as radiopharmaceuticals within 3 hr in 99% radiochemical purity

  8. Neurotensin analogs [D-TYR11] and [D-PHE11]neurotensin resist degradation by brain peptidases in vitro and in vivo

    International Nuclear Information System (INIS)

    Checler, F.; Vincent, J.P.; Kitabgi, P.

    1983-01-01

    The present study was designed to compare the susceptibility of neurotensin (NT), [ 3 H]NT, [D-Tyr11]NT and [D-Phe11]NT to degradation by 1) rat brain synaptic membranes in vitro and 2) after i.c.v. administration in the rat in vivo. Degradation was assessed by purifying the peptides using reverse phase high-performance liquid chromatography and by measuring the amount of radioactive or absorbing (OD 230) material under each peptide peak. In contrast to NT, [D-Tyr11]NT and [D-Phe11]NT were resistant to degradation by brain synaptic peptidases in vitro. Furthermore, NT was rapidly metabolized in brain tissues after i.c.v. administration, whereas [D-Tyr11]NT was metabolically stable. The present data confirm the central role of NT residue Tyr11 in the mechanisms of NT inactivation by brain synaptic peptidases. They account for the higher in vivo potency of [D-Tyr11]NT as compared with its in vitro potency. Finally, they explain, at least in part, the need to administer large doses of NT in the brain in order to observe neurobehavioral and neuropharmacological effects

  9. Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies

    International Nuclear Information System (INIS)

    Lacan, Goran; Way, Baldwin M.; Plenevaux, Alain; Defraiteur, Caroline; Lemaire, Christian; Aerts, Joel; Luxen, Andre; Rubins, Daniel J.; Cherry, Simon R.; Melega, William P.

    2008-01-01

    Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2''-pyridinyl)-p-[ 18 F] fluorobenzamido] ethylpiper azine ([ 18 F]MPPF) for binding to hydroxytryptamine 1A (5-HT 1A ) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies. Each Sprague-Dawley rat (n=4) received a baseline [ 18 F]MPPF microPET scan followed by second scan 2-3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.p.). Maximum a posteriori reconstructed images and volumetric ROIs were used to generate dynamic radioactivity concentration measurements for hippocampus, striatum, and cerebellum, with simplified reference tissue method (SRTM) analysis. Western blots were used to semiquantify P-gp regional distribution in brain. MicroPET studies showed that hippocampus uptake of [ 18 F]MPPF was increased after cyclosporine; ex vivo studies showed similar increases in hippocampus and frontal cortex at 30 min, and for heart and kidney at 2.5 and 5 min, without concomitant increases in [ 18 F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex. These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [ 18 F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [ 18 F]MPPF binding to 5-HT 1A receptors can be imaged in rat hippocampus. The heterogeneous brain distribution of P-gp appeared to invalidate the use of cerebellum as a nonspecific reference region for SRTM modeling. Regional quantitation of P-gp may be necessary for accurate PET assessment of 5-HT 1A receptor density when based on tracer uptake sensitive to P-gp modulation. (orig.)

  10. Specific in vivo binding in the rat brain of [18F]RP 62203: A selective 5-HT2A receptor radioligand for positron emission tomography

    International Nuclear Information System (INIS)

    Besret, Laurent; Dauphin, Francois; Huard, Cecile; Lasne, Marie-Claire; Vivet, Richard; Mickala, Patrick; Barbelivien, Alexandra; Baron, Jean-Claude

    1996-01-01

    In vivo pharmacokinetic and brain binding characteristics of [ 18 F]RP 62203, a selective high-affinity serotonergic 5-HT 2A receptor antagonist, were assessed in the rat following intravenous injection of trace amount of the radioligand. The radioactive distribution profile observed in the brain 60 min after injection was characterized by greater than fourfold higher uptake in neocortex as compared to cerebellum (0.38 ± 0.07% injected dose/g, % ID/g and 0.08 ± 0.01 ID/g, respectively), consistent with in vivo specific binding to the 5-HT 2A receptor. Furthermore, specific [ 18 F]RP 62203 binding significantly correlated with the reported in vitro distribution of 5-HT 2A receptors, but not with known concentration profiles of dopaminergic D 2 or adrenergic α 1 receptors. Finally, detectable specific binding was abolished by pretreatment with large doses of ritanserin, a selective 5-HT 2A antagonist, which resulted in uniform uptakes across cortical, striatal and cerebellar tissues. Thus, [ 18 F]RP 62203 appears to be a promising selective tool to visualize and quantify 5-HT 2A brain receptors in vivo with positron emission tomography

  11. In-vivo characteristics of high and low specific activity radioiodinated (+)-2-[4-(4-iodophenyl) piperidino] cyclohexanol [(+)-pIV] for imaging sigma-1 receptor in brain

    International Nuclear Information System (INIS)

    Akhter, Nasima; Kinuya, Seigo; Nakajima, Kenichi; Shiba, Kazuhiro; Ogawa, Kazuma; Mori, Hirofumi

    2007-01-01

    Full text: In this study, (+)-enantiomer of radioiodinated 2-[4-(4- iodophenyl)piperidino]cyclohexanol ((+)-[ 125 I]-p- iodovesamicol) [(+)-[ 125 I]pIV], which is reported to bind with high affinity to the sigma-1 receptor both in vitro and in vivo, was tested to compare the in vivo characteristics between high and low specific activity (+)-[ 125 I]pIV to image sigma-1 receptor in the central nervous system. In the biodistribution study, no significant difference was observed between two methods. Accumulation of (+)- [ 125 I]pIV in rat brain was significant (approximately 3% of the injected dose) and its retention was prolonged. In the blocking study, the accumulation of (+)-[ 125 I] pIV in the rat brain was significantly reduced by the co-administration of sigma ligands such as pentazocine, haloperidol or SA4503 in both methods. But the blocking effect was relatively stronger in the study using high specific activity radioiodinated (+)pIV. Though, the distribution of high and low specific activity (+)-[ 125 I] pIV was more or less similar to bind to sigma-1 receptor in the central nervous system in vivo, high specific activity radioiodinated (+) pIV might have a better specificity to bind sigma-1 receptor in brain. (author)

  12. Intranasal administration of human MSC for ischemic brain injury in the mouse: in vitro and in vivo neuroregenerative functions.

    Directory of Open Access Journals (Sweden)

    Vanessa Donega

    Full Text Available Intranasal treatment with C57BL/6 MSCs reduces lesion volume and improves motor and cognitive behavior in the neonatal hypoxic-ischemic (HI mouse model. In this study, we investigated the potential of human MSCs (hMSCs to treat HI brain injury in the neonatal mouse. Assessing the regenerative capacity of hMSCs is crucial for translation of our knowledge to the clinic. We determined the neuroregenerative potential of hMSCs in vitro and in vivo by intranasal administration 10 d post-HI in neonatal mice. HI was induced in P9 mouse pups. 1×10(6 or 2×10(6 hMSCs were administered intranasally 10 d post-HI. Motor behavior and lesion volume were measured 28 d post-HI. The in vitro capacity of hMSCs to induce differentiation of mouse neural stem cell (mNSC was determined using a transwell co-culture differentiation assay. To determine which chemotactic factors may play a role in mediating migration of MSCs to the lesion, we performed a PCR array on 84 chemotactic factors 10 days following sham-operation, and at 10 and 17 days post-HI. Our results show that 2×10(6 hMSCs decrease lesion volume, improve motor behavior, and reduce scar formation and microglia activity. Moreover, we demonstrate that the differentiation assay reflects the neuroregenerative potential of hMSCs in vivo, as hMSCs induce mNSCs to differentiate into neurons in vitro. We also provide evidence that the chemotactic factor CXCL10 may play an important role in hMSC migration to the lesion site. This is suggested by our finding that CXCL10 is significantly upregulated at 10 days following HI, but not at 17 days after HI, a time when MSCs no longer reach the lesion when given intranasally. The results described in this work also tempt us to contemplate hMSCs not only as a potential treatment option for neonatal encephalopathy, but also for a plethora of degenerative and traumatic injuries of the nervous system.

  13. Evaluation of the binding of the radiolabeled antidepressant drug, {sup 18}F-fluoxetine in the rodent brain: an in vitro and in vivo study

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, Jogeshwar E-mail: jogeshwar_mukherjee@ketthealth.com; Das, Malay K.; Yang Zhiying; Lew, Robert

    1998-10-01

    We have developed {sup 18}F-fluoxetine as a radiotracer analog of the antidepressant drug fluoxetine (Prozac). In vitro saturation experiments of {sup 18}F-fluoxetine were carried out on rat midbrain tissue and citalopram was used for measuring nonspecific binding. A saturation curve for the binding of {sup 18}F-fluoxetine was not obtained. Even when fluoxetine (10 {mu}M) was used for measurements of nonspecific binding, a saturation curve was difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and reserpine were also not able to reduce the binding of {sup 18}F-fluoxetine. Ex vivo autoradiographic experiments with {sup 18}F-fluoxetine did not reveal any specific uptake in various brain regions. In vivo administration of {sup 18}F-fluoxetine in rats showed similar uptake in all the brain regions with little regional selectivity. A subcellular analysis of rat brain tissue after intravenous (IV) administration of {sup 18}F-fluoxetine indicated significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro experiments with {sup 18}F-fluoxetine indicate little specific binding. Binding to the serotonin transporter was not identifiable. High nonspecific binding of the tracer resulting from its subcellular nature in the brain masks the ability to detect binding to the serotonin uptake sites in vivo. These findings indicate that a large portion of the binding of {sup 18}F-fluoxetine in rat brains is subcellular and clears slowly out of the cells. Other sites, such as monoamine oxidase, may also play a significant role in the action of fluoxetine.

  14. Evaluation of the binding of the radiolabeled antidepressant drug, 18F-fluoxetine in the rodent brain: an in vitro and in vivo study

    International Nuclear Information System (INIS)

    Mukherjee, Jogeshwar; Das, Malay K.; Yang Zhiying; Lew, Robert

    1998-01-01

    We have developed 18 F-fluoxetine as a radiotracer analog of the antidepressant drug fluoxetine (Prozac). In vitro saturation experiments of 18 F-fluoxetine were carried out on rat midbrain tissue and citalopram was used for measuring nonspecific binding. A saturation curve for the binding of 18 F-fluoxetine was not obtained. Even when fluoxetine (10 μM) was used for measurements of nonspecific binding, a saturation curve was difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and reserpine were also not able to reduce the binding of 18 F-fluoxetine. Ex vivo autoradiographic experiments with 18 F-fluoxetine did not reveal any specific uptake in various brain regions. In vivo administration of 18 F-fluoxetine in rats showed similar uptake in all the brain regions with little regional selectivity. A subcellular analysis of rat brain tissue after intravenous (IV) administration of 18 F-fluoxetine indicated significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro experiments with 18 F-fluoxetine indicate little specific binding. Binding to the serotonin transporter was not identifiable. High nonspecific binding of the tracer resulting from its subcellular nature in the brain masks the ability to detect binding to the serotonin uptake sites in vivo. These findings indicate that a large portion of the binding of 18 F-fluoxetine in rat brains is subcellular and clears slowly out of the cells. Other sites, such as monoamine oxidase, may also play a significant role in the action of fluoxetine

  15. In vivo binding of 125I-LSD to serotonin 5-HT2 receptors in mouse brain

    International Nuclear Information System (INIS)

    Hartig, P.R.; Scheffel, U.; Frost, J.J.; Wagner, H.N. Jr.

    1985-01-01

    The binding of 125 I-LSD (2-[ 125 I]-lysergic acid diethylamide) was studied in various mouse brain regions following intravenous injection of the radioligand. The high specific activity of 125 I-LSD enabled the injection of low mass doses (14ng/kg), which are well below the threshold for induction of any known physiological effect of the probe. The highest levels of 125 I-LSD binding were found in the frontal cortex, olfactory tubercles, extra-frontal cortex and striatum while the lowest level was found in the cerebellum. Binding was saturable in the frontal cortex but increased linearly in the cerebellum with increasing doses of 125 I-LSD. Serotonergic compounds potently inhibited 125 I-LSD binding in cortical regions, olfactory tubercles, and hypothalamus but had no effect in the cerebellum. Dopaminergic compounds caused partial inhibition of binding in the striatum while adrenergic compounds were inactive. From these studies the authors conclude that 125 I-LSD labels serotonin 5-HT 2 receptor sites in cortical regions with no indication that other receptor sites are labeled. In the olfactory tubercles and hypothalamus, 125 I-LSD labeling occurs predominantly or entirely at serotonic 5-HT 2 sites. In the striatum, 125 I-LSD labels approximately equal proportions of serotonergic and dopaminergic sites. These data indicate that 125 I-LSD labels serotonin receptors in vivo and suggests that appropriate derivatives of 2I-LSD may prove useful for tomographic imaging of serotonin 5-HT 2 receptors in the mammalian cortex

  16. Quantitative in vivo detection of brain cell death after hypoxia ischemia using the lipid peak at 1.3 ppm of proton magnetic resonance spectroscopy in neonatal rats.

    Science.gov (United States)

    Ahn, So Yoon; Yoo, Hye Soo; Lee, Jang Hoon; Sung, Dong Kyung; Jung, Yu Jin; Sung, Se In; Lim, Keun Ho; Chang, Yun Sil; Lee, Jung Hee; Kim, Ki Soo; Park, Won Soon

    2013-07-01

    This study was performed to determine the accuracy of proton magnetic spectroscopy ((1)H-MRS) lipid peak as a noninvasive tool for quantitative in vivo detection of brain cell death. Seven day-old Sprague Dawley rats were subjected to 8% oxygen following a unilateral carotid artery ligation. For treatment, cycloheximide was given immediately after hypoxic ischemia (HI). Lipid peak was measured using (1)H-MRS at 24 hr after HI, and then brains were harvested for fluorocytometric analyses with annexin V/propidium iodide (PI) and fluorescent probe JC-1, and for adenosine-5'-triphosphate (ATP) and lactate. Increased lipid peak at 1.3 ppm measured with (1)H-MRS, apoptotic and necrotic cells, and loss of mitochondrial membrane potential (ΔΨ) at 24 hr after HI were significantly improved with cycloheximide treatment. Significantly reduced brain ATP and increased lactate levels observed at 24 hr after HI showed a tendency to improve without statistical significance with cycloheximide treatment. Lipid peak at 1.3 ppm showed significant positive correlation with both apoptotic and necrotic cells and loss of ΔΨ, and negative correlation with normal live cells. Lipid peak at 1.3 ppm measured by (1)H-MRS might be a sensitive and reliable diagnostic tool for quantitative in vivo detection of brain cell death after HI.

  17. The gene expression of the neuronal protein, SLC38A9, changes in mouse brain after in vivo starvation and high-fat diet.

    Directory of Open Access Journals (Sweden)

    Sofie V Hellsten

    Full Text Available SLC38A9 is characterized as a lysosomal component of the amino acid sensing Ragulator-RAG GTPase complex, controlling the mechanistic target of rapamycin complex 1 (mTORC1. Here, immunohistochemistry was used to map SLC38A9 in mouse brain and staining was detected throughout the brain, in cortex, hypothalamus, thalamus, hippocampus, brainstem and cerebellum. More specifically, immunostaining was found in areas known to be involved in amino acid sensing and signaling pathways e.g. piriform cortex and hypothalamus. SLC38A9 immunoreactivity co-localized with both GABAergic and glutamatergic neurons, but not with astrocytes. SLC38A9 play a key role in the mTORC1 pathway, and therefore we performed in vivo starvation and high-fat diet studies, to measure gene expression alterations in specific brain tissues and in larger brain regions. Following starvation, Slc38a9 was upregulated in brainstem and cortex, and in anterior parts of the brain (Bregma 3.2 to -2.1mm. After high-fat diet, Slc38a9 was specifically upregulated in hypothalamus, while overall downregulation was noticed throughout the brain (Bregma 3.2 to -8.6mm.

  18. Radioligand binding analysis of α 2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding.

    Science.gov (United States)

    Phan, Jenny-Ann; Landau, Anne M; Jakobsen, Steen; Wong, Dean F; Gjedde, Albert

    2017-11-22

    We describe a novel method of kinetic analysis of radioligand binding to neuroreceptors in brain in vivo, here applied to noradrenaline receptors in rat brain. The method uses positron emission tomography (PET) of [ 11 C]yohimbine binding in brain to quantify the density and affinity of α 2 adrenoceptors under condition of changing radioligand binding to plasma proteins. We obtained dynamic PET recordings from brain of Spraque Dawley rats at baseline, followed by pharmacological challenge with unlabeled yohimbine (0.3 mg/kg). The challenge with unlabeled ligand failed to diminish radioligand accumulation in brain tissue, due to the blocking of radioligand binding to plasma proteins that elevated the free fractions of the radioligand in plasma. We devised a method that graphically resolved the masking of unlabeled ligand binding by the increase of radioligand free fractions in plasma. The Extended Inhibition Plot introduced here yielded an estimate of the volume of distribution of non-displaceable ligand in brain tissue that increased with the increase of the free fraction of the radioligand in plasma. The resulting binding potentials of the radioligand declined by 50-60% in the presence of unlabeled ligand. The kinetic unmasking of inhibited binding reflected in the increase of the reference volume of distribution yielded estimates of receptor saturation consistent with the binding of unlabeled ligand.

  19. Amyloid-β Plaques in Clinical Alzheimer’s Disease Brain Incorporate Stable Isotope Tracer In Vivo and Exhibit Nanoscale Heterogeneity

    Science.gov (United States)

    Wildburger, Norelle C.; Gyngard, Frank; Guillermier, Christelle; Patterson, Bruce W.; Elbert, Donald; Mawuenyega, Kwasi G.; Schneider, Theresa; Green, Karen; Roth, Robyn; Schmidt, Robert E.; Cairns, Nigel J.; Benzinger, Tammie L. S.; Steinhauser, Matthew L.; Bateman, Randall J.

    2018-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder with clinical manifestations of progressive memory decline and loss of executive function and language. AD affects an estimated 5.3 million Americans alone and is the most common form of age-related dementia with a rapidly growing prevalence among the aging population—those 65 years of age or older. AD is characterized by accumulation of aggregated amyloid-beta (Aβ) in the brain, which leads to one of the pathological hallmarks of AD—Aβ plaques. As a result, Aβ plaques have been extensively studied after being first described over a century ago. Advances in brain imaging and quantitative measures of Aβ in biological fluids have yielded insight into the time course of plaque development decades before and after AD symptom onset. However, despite the fundamental role of Aβ plaques in AD, in vivo measures of individual plaque growth, growth distribution, and dynamics are still lacking. To address this question, we combined stable isotope labeling kinetics (SILK) and nanoscale secondary ion mass spectrometry (NanoSIMS) imaging in an approach termed SILK–SIMS to resolve plaque dynamics in three human AD brains. In human AD brain, plaques exhibit incorporation of a stable isotope tracer. Tracer enrichment was highly variable between plaques and the spatial distribution asymmetric with both quiescent and active nanometer sub-regions of tracer incorporation. These data reveal that Aβ plaques are dynamic structures with deposition rates over days indicating a highly active process. Here, we report the first, direct quantitative measures of in vivo deposition into plaques in human AD brain. Our SILK–SIMS studies will provide invaluable information on plaque dynamics in the normal and diseased brain and offer many new avenues for investigation into pathological mechanisms of the disease, with implications for therapeutic development. PMID:29623063

  20. Amyloid-β Plaques in Clinical Alzheimer’s Disease Brain Incorporate Stable Isotope Tracer In Vivo and Exhibit Nanoscale Heterogeneity

    Directory of Open Access Journals (Sweden)

    Norelle C. Wildburger

    2018-03-01

    Full Text Available Alzheimer’s disease (AD is a neurodegenerative disorder with clinical manifestations of progressive memory decline and loss of executive function and language. AD affects an estimated 5.3 million Americans alone and is the most common form of age-related dementia with a rapidly growing prevalence among the aging population—those 65 years of age or older. AD is characterized by accumulation of aggregated amyloid-beta (Aβ in the brain, which leads to one of the pathological hallmarks of AD—Aβ plaques. As a result, Aβ plaques have been extensively studied after being first described over a century ago. Advances in brain imaging and quantitative measures of Aβ in biological fluids have yielded insight into the time course of plaque development decades before and after AD symptom onset. However, despite the fundamental role of Aβ plaques in AD, in vivo measures of individual plaque growth, growth distribution, and dynamics are still lacking. To address this question, we combined stable isotope labeling kinetics (SILK and nanoscale secondary ion mass spectrometry (NanoSIMS imaging in an approach termed SILK–SIMS to resolve plaque dynamics in three human AD brains. In human AD brain, plaques exhibit incorporation of a stable isotope tracer. Tracer enrichment was highly variable between plaques and the spatial distribution asymmetric with both quiescent and active nanometer sub-regions of tracer incorporation. These data reveal that Aβ plaques are dynamic structures with deposition rates over days indicating a highly active process. Here, we report the first, direct quantitative measures of in vivo deposition into plaques in human AD brain. Our SILK–SIMS studies will provide invaluable information on plaque dynamics in the normal and diseased brain and offer many new avenues for investigation into pathological mechanisms of the disease, with implications for therapeutic development.

  1. Estimate the time varying brain receptor occupancy in PET imaging experiments using non-linear fixed and mixed effect modeling approach

    International Nuclear Information System (INIS)

    Zamuner, Stefano; Gomeni, Roberto; Bye, Alan

    2002-01-01

    Positron-Emission Tomography (PET) is an imaging technology currently used in drug development as a non-invasive measure of drug distribution and interaction with biochemical target system. The level of receptor occupancy achieved by a compound can be estimated by comparing time-activity measurements in an experiment done using tracer alone with the activity measured when the tracer is given following administration of unlabelled compound. The effective use of this surrogate marker as an enabling tool for drug development requires the definition of a model linking the brain receptor occupancy with the fluctuation of plasma concentrations. However, the predictive performance of such a model is strongly related to the precision on the estimate of receptor occupancy evaluated in PET scans collected at different times following drug treatment. Several methods have been proposed for the analysis and the quantification of the ligand-receptor interactions investigated from PET data. The aim of the present study is to evaluate alternative parameter estimation strategies based on the use of non-linear mixed effect models allowing to account for intra and inter-subject variability on the time-activity and for covariates potentially explaining this variability. A comparison of the different modeling approaches is presented using real data. The results of this comparison indicates that the mixed effect approach with a primary model partitioning the variance in term of Inter-Individual Variability (IIV) and Inter-Occasion Variability (IOV) and a second stage model relating the changes on binding potential to the dose of unlabelled drug is definitely the preferred approach

  2. Source Reconstruction of Brain Potentials Using Bayesian Model Averaging to Analyze Face Intra-Domain vs. Face-Occupation Cross-Domain Processing.

    Science.gov (United States)

    Olivares, Ela I; Lage-Castellanos, Agustín; Bobes, María A; Iglesias, Jaime

    2018-01-01

    We investigated the neural correlates of the access to and retrieval of face structure information in contrast to those concerning the access to and retrieval of person-related verbal information, triggered by faces. We experimentally induced stimulus familiarity via a systematic learning procedure including faces with and without associated verbal information. Then, we recorded event-related potentials (ERPs) in both intra-domain (face-feature) and cross-domain (face-occupation) matching tasks while N400-like responses were elicited by incorrect eyes-eyebrows completions and occupations, respectively. A novel Bayesian source reconstruction approach plus conjunction analysis of group effects revealed that in both cases the generated N170s were of similar amplitude but had different neural origin. Thus, whereas the N170 of faces was associated predominantly to right fusiform and occipital regions (the so-called "Fusiform Face Area", "FFA" and "Occipital Face Area", "OFA", respectively), the N170 of occupations was associated to a bilateral very posterior activity, suggestive of basic perceptual processes. Importantly, the right-sided perceptual P200 and the face-related N250 were evoked exclusively in the intra-domain task, with sources in OFA and extensively in the fusiform region, respectively. Regarding later latencies, the intra-domain N400 seemed to be generated in right posterior brain regions encompassing mainly OFA and, to some extent, the FFA, likely reflecting neural operations triggered by structural incongruities. In turn, the cross-domain N400 was related to more anterior left-sided fusiform and temporal inferior sources, paralleling those described previously for the classic verbal N400. These results support the existence of differentiated neural streams for face structure and person-related verbal processing triggered by faces, which can be activated differentially according to specific task demands.

  3. Source Reconstruction of Brain Potentials Using Bayesian Model Averaging to Analyze Face Intra-Domain vs. Face-Occupation Cross-Domain Processing

    Directory of Open Access Journals (Sweden)

    Ela I. Olivares

    2018-03-01

    Full Text Available We investigated the neural correlates of the access to and retrieval of face structure information in contrast to those concerning the access to and retrieval of person-related verbal information, triggered by faces. We experimentally induced stimulus familiarity via a systematic learning procedure including faces with and without associated verbal information. Then, we recorded event-related potentials (ERPs in both intra-domain (face-feature and cross-domain (face-occupation matching tasks while N400-like responses were elicited by incorrect eyes-eyebrows completions and occupations, respectively. A novel Bayesian source reconstruction approach plus conjunction analysis of group effects revealed that in both cases the generated N170s were of similar amplitude but had different neural origin. Thus, whereas the N170 of faces was associated predominantly to right fusiform and occipital regions (the so-called “Fusiform Face Area”, “FFA” and “Occipital Face Area”, “OFA”, respectively, the N170 of occupations was associated to a bilateral very posterior activity, suggestive of basic perceptual processes. Importantly, the right-sided perceptual P200 and the face-related N250 were evoked exclusively in the intra-domain task, with sources in OFA and extensively in the fusiform region, respectively. Regarding later latencies, the intra-domain N400 seemed to be generated in right posterior brain regions encompassing mainly OFA and, to some extent, the FFA, likely reflecting neural operations triggered by structural incongruities. In turn, the cross-domain N400 was related to more anterior left-sided fusiform and temporal inferior sources, paralleling those described previously for the classic verbal N400. These results support the existence of differentiated neural streams for face structure and person-related verbal processing triggered by faces, which can be activated differentially according to specific task demands.

  4. Association Between Brain Gene Expression, DNA Methylation, and Alteration of Ex Vivo Magnetic Resonance Imaging Transverse Relaxation in Late-Life Cognitive Decline.

    Science.gov (United States)

    Yu, Lei; Dawe, Robert J; Boyle, Patricia A; Gaiteri, Chris; Yang, Jingyun; Buchman, Aron S; Schneider, Julie A; Arfanakis, Konstantinos; De Jager, Philip L; Bennett, David A

    2017-12-01

    Alteration of ex vivo magnetic resonance imaging transverse relaxation is associated with late-life cognitive decline even after controlling for common neuropathologic conditions. However, the underlying neurobiology of this association is unknown. To investigate the association between brain gene expression, DNA methylation, and alteration of magnetic resonance imaging transverse relaxation in late-life cognitive decline. Data came from 2 community-based longitudinal cohort studies of aging and dementia, the Religious Orders Study, which began in 1993, and the Rush Memory and Aging Project, which began in 1997. All participants agreed to undergo annual clinical evaluations and to donate their brains after death. By October 24, 2016, a total of 1358 individuals had died and had brain autopsies that were approved by board-certified neuropathologists. Of those, 552 had undergone ex vivo imaging. The gene expression analysis was limited to 174 individuals with both imaging and brain RNA sequencing data. The DNA methylation analysis was limited to 225 individuals with both imaging and brain methylation data. Maps of ex vivo magnetic resonance imaging transverse relaxation were generated using fast spin echo imaging. The target was a composite measure of the transverse relaxation rate (R2) that was associated with cognitive decline after controlling for common neuropathologic conditions. Next-generation RNA sequencing and DNA methylation data were generated using frozen tissue from the dorsolateral prefrontal cortex. Genome-wide association analysis was used to investigate gene expression and, separately, DNA methylation for signals associated with the R2 measure. Of the 552 individuals with ex vivo imaging data, 394 were women and 158 were men, and the mean (SD) age at death was 90.4 (6.0) years. Four co-expressed genes (PADI2 [Ensembl ENSG00000117115], ZNF385A [Ensembl ENSG00000161642], PSD2 [Ensembl ENSG00000146005], and A2ML1 [Ensembl ENSG00000166535]) were

  5. Development of self-awareness after severe traumatic brain injury through participation in occupation-based rehabilitation: mixed-methods analysis of a case series.

    Science.gov (United States)

    Doig, Emmah; Kuipers, Pim; Prescott, Sarah; Cornwell, Petrea; Fleming, Jennifer

    2014-01-01

    OBJECTIVE. We examined participation in goal planning and development of self-awareness for people with impaired self-awareness after traumatic brain injury. METHOD. We performed a mixed-methods study of 8 participants recently discharged from inpatient rehabilitation. Self-awareness was measured using discrepancy between self and significant other ratings on the Mayo-Portland Adaptability Index (MPAI-4) at four time points. We calculated effect size to evaluate the change in MPAI-4 discrepancy over time. RESULTS. Seven participants identified their own goals. We found a large reduction in mean MPAI-4 discrepancy (M = 8.57, SD = 6.59, N = 7, d = 1.08) in the first 6 wk and a further small reduction (M = 5.33, SD = 9.09, N = 6, d = 0.45) in the second 6 wk of intervention. Case data indicated that 7 participants demonstrated some growth in self-awareness. CONCLUSION. Engagement in occupation-based, goal-directed rehabilitation appeared to foster awareness of injury-related changes to varying extents. Copyright © 2014 by the American Occupational Therapy Association, Inc.

  6. Occupational exposure to electromagnetic fields, leukemia and brain cancer: update of two meta-analysis; Exposition professionnelle aux champs electromagnetiques, leucemie et cancer du cerveau: mise a jour de deux meta-analyses

    Energy Technology Data Exchange (ETDEWEB)

    Anon

    2008-11-15

    This new meta-analysis found a slight increase in the risk of brain cancer and of leukemia in populations occupationally exposed to electromagnetic fields. it does not, however, support the hypothesis that electromagnetic fields have an effect on these cancers. (author)

  7. A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype

    International Nuclear Information System (INIS)

    Gitler, M.S.; Cohen, V.I.; De La Cruz, R.; Boulay, S.F.; Jin, B.; Zeeberg, B.R.; Reba, R.C.

    1993-01-01

    Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. In our efforts to prepare such a radioligand, the authors have used competition studies against currently existing muscarinic receptor radioligands to infer the in vitro and in vivo properties of a novel muscarinic receptor ligand, 5-[[4-[4-(diisobutylamino)butyl]-1-phenyl]acetyl]-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one (DIBD). In vitro competition studies against [ 3 H](R)-3-quinuclidinylbenzilate ([ 3 H]QNB) and [ 3 H]N-methylscopolamine ([ 3 H]NMS), using membranes derived from transfected cells expressing only m1, m2, m3, or m4 receptor subtypes, indicate that DIBD is selective for m2/m4 over m1/m3. In vivo competition studies against (R,R)-[ 125 I]IQNB indicate that DIBD crosses the blood brain barrier (BBB). The relationship of the regional percentage decrease in (R,R)-[ 125 I]IQNB versus the percentage of each of the receptor subtypes indicates that DIBD competes more effectively in those brain regions which are known to be enriched in the m2, relative to the m1, m3, and m4, receptor subtype; however, analysis of the data using a mathematical model shows that caution is required when interpreting the in vivo results. The authors conclude that a suitably radiolabeled derivative of DIBD may be of potential use in emission tomographic study of changes in m2 receptors in the central nervous system

  8. In vivo imaging of serotonin transporter occupancy by means of SPECT and [123I]ADAM in healthy subjects administered different doses of escitalopram or citalopram.

    Science.gov (United States)

    Klein, N; Sacher, J; Geiss-Granadia, T; Attarbaschi, T; Mossaheb, N; Lanzenberger, R; Pötzi, C; Holik, A; Spindelegger, C; Asenbaum, S; Dudczak, R; Tauscher, J; Kasper, S

    2006-10-01

    Escitalopram is a dual serotonin reuptake inhibitor (SSRI) approved for the treatment of depression and anxiety disorders. It is the S-enantiomer of citalopram, and is responsible for the serotonin reuptake activity, and thus for its pharmacological effects. Previous studies pointed out that clinically efficacious doses of other SSRIs produce an occupancy of the serotonin reuptake transporter (SERT) of about 80% or more. The novel radioligand [123I]ADAM and single photon emission computer tomography (SPECT) were used to measure midbrain SERT occupancies for different doses of escitalopram and citalopram. Twenty-five healthy subjects received a single dose of escitalopram [5 mg (n=5), 10 mg (n=5), and 20 mg (n=5)] or citalopram [(10 mg (n=5) and 20 mg (n=5)]. Midbrain SERT binding was measured with [(123)I]ADAM and SPECT on two study days, once without study drug and once 6 h after single dose administration of the study drug. The ratio of midbrain-cerebellum/cerebellum was the outcome measure (V3") for specific binding to SERT in midbrain. Subsequently, SERT occupancy levels were calculated using the untreated baseline level for each subject. An Emax model was used to describe the relationship between S-citalopram concentrations and SERT occupancy values. Additionally, four subjects received placebo to determine test-retest variability. Single doses of 5, 10, or 20 mg escitalopram led to a mean SERT occupancy of 60+/-6, 64+/-6, and 75+/-5%, respectively. SERT occupancies for subjects treated with single doses of 10 and 20 mg citalopram were 65+/-10 and 70+/-6%, respectively. A statistically significant difference was found between SERT occupancies after application of 10 and 20 mg escitalopram, but not for 10 and 20 mg citalopram. There was no statistically significant difference between the SERT occupancies of either 10 mg citalopram or 10 mg escitalopram, or between 20 mg citalopram and 20 mg escitalopram. Emax was slightly higher after administration of

  9. FTIR Imaging of Brain Tissue Reveals Crystalline Creatine Deposits Are an ex Vivo Marker of Localized Ischemia during Murine Cerebral Malaria: General Implications for Disease Neurochemistry

    Science.gov (United States)

    2012-01-01

    Phosphocreatine is a major cellular source of high energy phosphates, which is crucial to maintain cell viability under conditions of impaired metabolic states, such as decreased oxygen and energy availability (i.e., ischemia). Many methods exist for the bulk analysis of phosphocreatine and its dephosphorylated product creatine; however, no method exists to image the distribution of creatine or phosphocreatine at the cellular level. In this study, Fourier transform infrared (FTIR) spectroscopic imaging has revealed the ex vivo development of creatine microdeposits in situ in the brain region most affected by the disease, the cerebellum of cerebral malaria (CM) diseased mice; however, such deposits were also observed at significantly lower levels in the brains of control mice and mice with severe malaria. In addition, the number of deposits was observed to increase in a time-dependent manner during dehydration post tissue cutting. This challenges the hypotheses in recent reports of FTIR spectroscopic imaging where creatine microdeposits found in situ within thin sections from epileptic, Alzheimer’s (AD), and amlyoid lateral sclerosis (ALS) diseased brains were proposed to be disease specific markers and/or postulated to contribute to the brain pathogenesis. As such, a detailed investigation was undertaken, which has established that the creatine microdeposits exist as the highly soluble HCl salt or zwitterion and are an ex-vivo tissue processing artifact and, hence, have no effect on disease pathogenesis. They occur as a result of creatine crystallization during dehydration (i.e., air-drying) of thin sections of brain tissue. As ischemia and decreased aerobic (oxidative metabolism) are common to many brain disorders, regions of elevated creatine-to-phosphocreatine ratio are likely to promote crystal formation during tissue dehydration (due to the lower water solubility of creatine relative to phosphocreatine). The results of this study have demonstrated that

  10. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier.

    Science.gov (United States)

    Molino, Yves; David, Marion; Varini, Karine; Jabès, Françoise; Gaudin, Nicolas; Fortoul, Aude; Bakloul, Karima; Masse, Maxime; Bernard, Anne; Drobecq, Lucile; Lécorché, Pascaline; Temsamani, Jamal; Jacquot, Guillaume; Khrestchatisky, Michel

    2017-05-01

    The blood-brain barrier (BBB) prevents the entry of many drugs into the brain and, thus, is a major obstacle in the treatment of CNS diseases. There is some evidence that the LDL receptor (LDLR) is expressed at the BBB and may participate in the transport of endogenous ligands from blood to brain, a process referred to as receptor-mediated transcytosis. We previously described a family of peptide vectors that were developed to target the LDLR. In the present study, in vitro BBB models that were derived from wild-type and LDLR-knockout animals ( ldlr -/- ) were used to validate the specific LDLR-dependent transcytosis of LDL via a nondegradative route. We next showed that LDLR-targeting peptide vectors, whether in fusion or chemically conjugated to an Ab Fc fragment, promote binding to apical LDLR and transendothelial transfer of the Fc fragment across BBB monolayers via the same route as LDL. Finally, we demonstrated in vivo that LDLR significantly contributes to the brain uptake of vectorized Fc. We thus provide further evidence that LDLR is a relevant receptor for CNS drug delivery via receptor-mediated transcytosis and that the peptide vectors we developed have the potential to transport drugs, including proteins or Ab based, across the BBB.-Molino, Y., David, M., Varini, K., Jabès, F., Gaudin, N., Fortoul, A., Bakloul, K., Masse, M., Bernard, A., Drobecq, L., Lécorché, P., Temsamani, J., Jacquot, G., Khrestchatisky, M. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier. © FASEB.

  11. Statistical parametric mapping for effects of verapamil on olfactory connections of rat brain in vivo using manganese-enhanced MR imaging

    International Nuclear Information System (INIS)

    Soma, Tsutomu; Kurakawa, Masami; Koto, Daichi

    2011-01-01

    We investigated the effect of verapamil on the transport of manganese in the olfactory connections of rat brains in vivo using statistical parametric mapping and manganese-enhanced magnetic resonance (MR) imaging. We divided 12 7-week-old male Sprague-Dawley rats into 2 groups of six and injected 10 μL of saline into the right nasal cavities of the first group and 10 μL of verapamil (2.5 mg/mL) into the other group. Twenty minutes after the initial injection, we injected 10 μL of MnCl 2 (1 mol/L) into the right nasal cavities of both groups. We obtained serial T 1 -weighted MR images before administering the verapamil or saline and at 0.5, one, 24, 48, and 72 hours and 7 days after administering the MnCl 2 , spatially normalized the MR images on the rat brain atlas, and analyzed the data using voxel-based statistical comparison. Statistical parametric maps demonstrated the transport of manganese. Manganese ions created significant enhancement (t-score=36.6) 24 hours after MnCl 2 administration in the group administered saline but not at the same time point in the group receiving verapamil. The extent of significantly enhanced regions peaked at 72 hours in both groups and both sides of the brain. The peak of extent in the right side brain in the group injected with saline was 70.2 mm 3 and in the group with verapamil, 92.4 mm 3 . The extents in the left side were 64.0 mm 3 for the group with saline and 53.2 mm 3 for the group with verapamil. We applied statistical parametric mapping using manganese-enhanced MR imaging to demonstrate in vivo the transport of manganese in the olfactory connections of rat brains with and without verapamil and found that verapamil did affect this transport. (author)

  12. An in vitro and in vivo study of peptide-functionalized nanoparticles for brain targeting : The importance of selective blood–brain barrier uptake

    NARCIS (Netherlands)

    Bode, Gerard H.; Coué, G.M.J.P.C.; Freese, Christian; Pickl, Karin E.; Sanchez-Purrà, Maria; Albaiges, Berta; Borrós, Salvador; van Winden, Ewoud C.; Tziveleka, Leto Aikaterini; Sideratou, Zili; Engbersen, Johan F.J.; Singh, Smriti; Albrecht, Krystyna; Groll, Jürgen; Möller, Martin; Pötgens, Andy J.G.; Schmitz, Christoph; Fröhlich, Eleonore; Grandfils, Christian; Sinner, Frank M.; Kirkpatrick, C. James; Steinbusch, Harry W.M.; Frank, Hans Georg; Unger, Ronald E.; Martinez-Martinez, Pilar

    2017-01-01

    Targeted delivery of drugs across endothelial barriers remains a formidable challenge, especially in the case of the brain, where the blood–brain barrier severely limits entry of drugs into the central nervous system. Nanoparticle-mediated transport of peptide/protein-based drugs across endothelial

  13. Melatonin reduces hypoxic-ischaemic (HI) induced autophagy and apoptosis: An in vivo and in vitro investigation in experimental models of neonatal HI brain injury.

    Science.gov (United States)

    Hu, Yingying; Wang, Zhouguang; Liu, Yanlong; Pan, Shulin; Zhang, Hao; Fang, Mingchu; Jiang, Huai; Yin, Jiayu; Zou, Shuangshuang; Li, Zhenmao; Zhang, Hongyu; Lin, Zhenlang; Xiao, Jian

    2017-07-13

    Melatonin has neuroprotective effects in many diseases, including neonatal hypoxic-ischaemic (HI) brain injury. The purpose of this study was to evaluate the neuroprotective effects of melatonin both in vivo and in vitro and associated molecular mechanisms behind these effects. Postnatal day 7 male and female rat pups were subjected to unilateral HI, melatonin was injected intraperitoneally 1h before HI and an additional six doses were administered at 24h intervals. The pups were sacrificed at 24h and 7 d after HI. Pre-treatment with melatonin significantly reduced brain damage at 7 d after HI, with 15mg/kg melatonin achieving over 30% recovery in tissue loss compared to vehicle-treated animals. Autophagy and apoptotic cell death as indicated by autophagy associated proteins, cleaved caspase 3 and Tunel staining, was significantly inhibited after melatonin treatment in vivo as well as in PC12 cells. Melatonin treatment also significantly increased the GAP43 in the cortex. In conclusion, melatonin treatment reduced neonatal rat brain injury after HI, and this appeared to be related to inhibiting autophagy as well as reducing apoptotic cell death. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. [Ferumoxide labeled Flk1+ CD31- CD34- human bone marrow mesenchymal stem cells and its in vivo tracing in the brains of Macaca Fascicularis].

    Science.gov (United States)

    Feng, Ming; Wang, Ren-Zhi; Zhu, Hua; Zhang, Nan; Wang, Chang-Jun; Wei, Jun-Ji; Lu, Shan; Li, Qin; Yin, Xiao-Ming; Han, Qin; Ma, Wen-Bin; Qin, Chuang; Zhao, Chun-Hua; An, Yi-Hua; Kong, Yan-Guo

    2008-10-01

    To explore the method for labeling Flk1+ CD31- CD34- human bone marrow mesenchymal stem cells (hBMSCs) with ferumoxide-PLL and evaluate the feasibility of its tracing after transplantation into the brains of Macaca Fascicularis. The hBMSCs were incubated with ferumoxide-PLL. Trypan blue staining, Prussian blue staining, and transmission electron microscope were performed to show intracellular iron, marking efficiency, and the vigor of the labeled cells. After the hBMSCs were transplanted into the brains of cynomolgus monkeys by stereotaxis, magnetic resonance imaging (MRI) was performed to trace the cells in vivo. Cell survival and differentiation were studied with immunohistochemistry, Prussian blue staining, and HE staining. The marking efficiency of the ferumoxide-PLL was 96%. Iron particles were found intracytoplasmic of the hBMSCs by Prussian blue staining and transmission electron microscopy. The relaxation rates of labeled cells in MRI were 4.4 and 4.2 times higher than those of the unlabeled cells. Hypointensity area was found by MRI three weeks after transplantation. Many hBMSCs and new vessels were found in the transplantation zone by pathological and immunofluorescence methods. Ferumoxide-PLL can effectively label hBMSCs and thus increase its contrast in MRI results. The cells can survive in the brains of cynomolgus monkeys. The labeled hBMSCs can be traced in vivo by MRI.

  15. Rate equation for creatine kinase predicts the in vivo reaction velocity: 31P NMR surface coil studies in brain, heart, and skeletal muscle of the living rat

    International Nuclear Information System (INIS)

    Bittl, J.A.; DeLayre, J.; Ingwall, J.S.

    1987-01-01

    Brain, heart, and skeletal muscle contain four different creatine kinase isozymes and various concentrations of substrates for the creatine kinase reaction. To identify if the velocity of the creatine kinase reaction under cellular conditions is regulated by enzyme activity and substrate concentrations as predicted by the rate equation, the authors used 31 P NMR and spectrophotometric techniques to measure reaction velocity, enzyme content, isozyme distribution, and concentrations of substrates in brain, heart, and skeletal muscle of living rat under basal or resting conditions. The total tissue activity of creatine kinase in the direction of MgATP synthesis provided an estimate for V/sub max/ and exceeded the NMR-determined in vivo reaction velocities by an order of magnitude. The isozyme composition varied among the three tissues: >99% BB for brain; 14% MB, 61% MM, and 25% mitochondrial for heart; and 98% MM and 2% mitochondrial for skeletal muscle. The NMR-determined reaction velocities agreed with predicted values from the creatine kinase rate equation. The concentrations of free creatine and cytosolic MgADP, being less than or equal to the dissociation constants for each isozyme, were dominant terms in the creatine kinase rate equation for predicting the in vivo reaction velocity. Thus, they observed that the velocity of the creatine kinase reaction is regulated by total tissue enzyme activity and by the concentrations of creatine and MgADP in a manner that is independent of isozyme distribution

  16. Transport of Glial Cell Line-Derived Neurotrophic Factor into Liposomes across the Blood-Brain Barrier: In Vitro and in Vivo Studies

    Directory of Open Access Journals (Sweden)

    Shaoling Wu

    2014-02-01

    Full Text Available Glial cell line-derived neurotrophic factor (GDNF was encapsulated into liposomes in order to protect it from enzyme degradation in vivo and promote its permeability across the blood-brain barrier (BBB. In this study, GDNF conventional liposomes (GDNF-L and GDNF target sterically stabilized liposomes (GDNF-SSL-T were prepared. The average size of liposomes was below 90 nm. A primary model of BBB was established and evaluated by transendothelial electrical resistance (TEER and permeability. This BBB model was employed to study the permeability of GDNF liposomes in vitro. The results indicated that the liposomes could enhance transport of GDNF across the BBB and GDNF-SSL-T had achieved the best transport efficacy. The distribution of GDNF liposomes was studied in vivo. Free GDNF and GDNF-L were eliminated rapidly in the circulation. GDNF-SSL-T has a prolonged circulation time in the blood and favorable brain delivery. The values of the area under the curve (AUC(0–1 h in the brain of GDNF-SSL-T was 8.1 times and 6.8 times more than that of free GDNF and GDNF-L, respectively. These results showed that GDNF-SSL-T realized the aim of targeted delivery of therapeutic proteins to central nervous system.

  17. In vivo optical microprobe imaging for intracellular Ca2+ dynamics in response to dopaminergic signaling in deep brain evoked by cocaine

    Science.gov (United States)

    Luo, Zhongchi; Pan, Yingtian; Du, Congwu

    2012-02-01

    Ca2+ plays a vital role as second messenger in signal transduction and the intracellular Ca2+ ([Ca2+]i) change is an important indicator of neuronal activity in the brain, including both cortical and subcortical brain regions. Due to the highly scattering and absorption of brain tissue, it is challenging to optically access the deep brain regions (e.g., striatum at >3mm under the brain surface) and image [Ca2+]i changes with cellular resolutions. Here, we present two micro-probe approaches (i.e., microlens, and micro-prism) integrated with a fluorescence microscope modified to permit imaging of neuronal [Ca2+]i signaling in the striatum using a calcium indicator Rhod2(AM). While a micro-prism probe provides a larger field of view to image neuronal network from cortex to striatum, a microlens probe enables us to track [Ca2+]i dynamic change in individual neurons within the brain. Both techniques are validated by imaging neuronal [Ca2+]i changes in transgenic mice with dopamine receptors (D1R, D2R) expressing EGFP. Our results show that micro-prism images can map the distribution of D1R- and D2R-expressing neurons in various brain regions and characterize their different mean [Ca2+]i changes induced by an intervention (e.g., cocaine administration, 8mg/kg., i.p). In addition, microlens images can characterize the different [Ca2+]i dynamics of D1 and D2 neurons in response to cocaine, including new mechanisms of these two types of neurons in striatum. These findings highlight the power of the optical micro-probe imaging for dissecting the complex cellular and molecular insights of cocaine in vivo.

  18. Regional blockade by neuroleptic drugs of in vivo /sup 3/H-spiperone binding in the rat brain. Relation to blockade of apomorphine induced hyperactivity and stereotypies

    Energy Technology Data Exchange (ETDEWEB)

    Koehler, C; Haglund, L; Oegren, S O; Aengeby, T [Astra Lackemedel AB, Soedertaelje (Sweden). Dept. of Pharmacology

    1981-01-01

    The regional prevention by neuroleptic drugs of specific in vivo /sup 3/H-spiperone binding was studied in the rat brain. L-sulpiride, thioridazine and clozapine were found to reduce the /sup 3/H-spiperone bindings selectively in the olfactory tubercle, septum, substantia nigra and frontal cortex but not the striatum at dose levels which preferentially block apomorphine (APO) induced hyperactivity. The maximal prevention of specific /sup 3/H-spiperone binding by l-sulpiride and clozapine reached 60-80% in the former structures while the displacement of striatal /sup 3/H-spiperone binding did not exceed 40%. In contrast to l-sulpiride, thioridazine and clozapine both chlorpromazine and haloperidol reduced the /sup 3/H-spiperone binding to the same extent in all regions studied. Chlorpromazine and haloperidol were potent in prevention of striatal /sup 3/H-spiperone binding in vivo which reached 60-80% in this structure.

  19. Regional blockade by neuroleptic drugs of in vivo 3H-spiperone binding in the rat brain. Relation to blockade of apomorphine induced hyperactivity and stereotypies

    International Nuclear Information System (INIS)

    Koehler, C.; Haglund, L.; Oegren, S.-O.; Aengeby, T.

    1981-01-01

    The regional prevention by neuroleptic drugs of specific in vivo 3 H-spiperone binding was studied in the rat brain. L-sulpiride, thioridazine and clozapine were found to reduce the 3 H-spiperone bindings selectively in the olfactory tubercle, septum, substantia nigra and frontal cortex but not the striatum at dose levels which preferentially block apomorphine (APO) induced hyperactivity. The maximal prevention of specific 3 H-spiperone binding by l-sulpiride and clozapine reached 60-80% in the former structures while the displacement of striatal 3 H-spiperone binding did not exceed 40%. In contrast to l-sulpiride, thioridazine and clozapine both chlorpromazine and haloperidol reduced the 3 H-spiperone binding to the same extent in all regions studied. Chlorpromazine and haloperidol were potent in prevention of striatal 3 H-spiperone binding in vivo which reached 60-80% in this structure. (Author)

  20. Application of optical coherence tomography for in vivo monitoring of the meningeal lymphatic vessels during opening of blood-brain barrier: mechanisms of brain clearing

    Science.gov (United States)

    Semyachkina-Glushkovskaya, Oxana; Abdurashitov, Arkady; Dubrovsky, Alexander; Bragin, Denis; Bragina, Olga; Shushunova, Nataliya; Maslyakova, Galina; Navolokin, Nikita; Bucharskaya, Alla; Tuchin, Valery; Kurths, Juergen; Shirokov, Alexander

    2017-12-01

    The meningeal lymphatic vessels were discovered 2 years ago as the drainage system involved in the mechanisms underlying the clearance of waste products from the brain. The blood-brain barrier (BBB) is a gatekeeper that strongly controls the movement of different molecules from the blood into the brain. We know the scenarios during the opening of the BBB, but there is extremely limited information on how the brain clears the substances that cross the BBB. Here, using the model of sound-induced opening of the BBB, we clearly show how the brain clears dextran after it crosses the BBB via the meningeal lymphatic vessels. We first demonstrate successful application of optical coherence tomography (OCT) for imaging of the lymphatic vessels in the meninges after opening of the BBB, which might be a new useful strategy for noninvasive analysis of lymphatic drainage in daily clinical practice. Also, we give information about the depth and size of the meningeal lymphatic vessels in mice. These new fundamental data with the applied focus on the OCT shed light on the mechanisms of brain clearance and the role of lymphatic drainage in these processes that could serve as an informative platform for a development of therapy and diagnostics of diseases associated with injuries of the BBB such as stroke, brain trauma, glioma, depression, or Alzheimer disease.

  1. 1H diffusion-weighted, 13C and 17O NMR spectroscopy: methodological developments to study brain structure and function in vivo

    International Nuclear Information System (INIS)

    Najac, Chloe

    2014-01-01

    Magnetic Resonance Spectroscopy is a unique tool that allows acquiring brain biochemical profiles and quantifying many cellular parameters in vivo. During this thesis, three different techniques have been developed: (i) 1 H diffusion-weighted, (ii) carbon-13 ( 13 C) and (iii) oxygen-17 ( 17 O) NMR spectroscopy to study brain structure and function in vivo. Brain metabolites are cell-specific endogenous tracers of the intracellular space whose translational diffusion depends on many cellular properties (e.g.: cytosol viscosity and intracellular restriction). Studying the variation of the diffusion coefficient (ADC) as a function of diffusion time (td) allows untangling and quantifying those parameters. In particular, measuring metabolites ADC at long diffusion times gives information about the metabolites compartmentation in cells. In a first study, we measured neuronal and astrocytic metabolites ADC over a large time window (from 80 ms to 1 s) in a large voxel in the macaque brain. No dependence of all metabolites ADC on td was observed suggesting that metabolites primarily diffuse in neuronal (dendrites and axons) and astrocytic processes and are not confined inside the cell body and organelles (nucleus, mitochondria). The large size of the voxel, due to low detection sensitivity, did not allow us to study metabolites compartmentation in pure white (WM) and grey matters (GM). Therefore, we performed a new study in the human brain. Results showed that in both WM and GM metabolites diffuse in fiber-like cell structure. Finally, using an even larger time window (up to 2 s) in the macaque brain and analytical models mimicking the cell structure, we estimated the length of neuronal (∼110 μm) and astrocytic (∼70 μm) processes. ATP (adenosine triphosphate), the main source of energy in the organism, is produced thanks to glucose oxidation inside the mitochondria. 13 C NMR spectroscopy is a well-known technique to study brain energy metabolism and can be used to

  2. Physiological neuronal decline in healthy aging human brain - An in vivo study with MRI and short echo-time whole-brain (1)H MR spectroscopic imaging.

    Science.gov (United States)

    Ding, Xiao-Qi; Maudsley, Andrew A; Sabati, Mohammad; Sheriff, Sulaiman; Schmitz, Birte; Schütze, Martin; Bronzlik, Paul; Kahl, Kai G; Lanfermann, Heinrich

    2016-08-15

    Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. To investigate neuronal decline in normal aging brain eighty-one healthy subjects aged between 20 and 70years were studied with MRI and whole-brain (1)H MR spectroscopic imaging. Concentrations of brain metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), and glutamine+glutamate (Glx) in ratios to internal water, and the fractional volumes of brain tissue were estimated simultaneously in eight cerebral lobes and in cerebellum. Results demonstrated that an age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Both lobar NAA and the fractional volume of gray matter (FVGM) decreased with age in all cerebral lobes, indicating that the decreased NAA was predominantly associated with decreased gray matter volume and neuronal density or metabolic activity. In cerebral white matter Cho, tCr, and mI increased with age in association with increased fractional volume, showing altered cellular membrane turn-over, energy metabolism, and glial activity in human aging white matter. In cerebellum tCr increased while brain tissue volume decreased with age, showing difference to cerebral aging. The observed age-related metabolic and microstructural variations suggest that physiological neuronal decline in aging human brain is associated with a reduction of gray matter volume and neuronal density, in combination with cellular aging in white matter indicated by microstructural alterations and altered energy metabolism in the cerebellum. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. In vivo magnetic resonance imaging and 31P spectroscopy of large human brain tumours at 1.5 tesla

    DEFF Research Database (Denmark)

    Thomsen, C; Jensen, K E; Achten, E

    1988-01-01

    31P MR spectroscopy of human brain tumours is one feature of magnetic resonance imaging. Eight patients with large superficial brain tumours and eight healthy volunteers were examined with 31P spectroscopy using an 8 cm surface coil for volume selection. Seven frequencies were resolved in our spe...

  4. Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression.

    Directory of Open Access Journals (Sweden)

    Dongsha Wang

    Full Text Available The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET measures of brain serotonin (5-HT synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC. Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25 who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20 where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.

  5. Brain delivery of camptothecin by means of solid lipid nanoparticles: Formulation design, in vitro and in vivo studies

    DEFF Research Database (Denmark)

    Martins, S.; Tho, I.; Reimold, I.

    2012-01-01

    that fluorescently labelled SLN were detected in the brain after i.v. administration. This study indicates that the camptothecin-loaded SLN are a promising drug brain delivery system worth to explore further for brain tumour therapy. (C) 2012 Elsevier B. V. All rights reserved.......For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded solid lipid nanoparticles (SLN), prepared by hot high pressure homogenisation, were designed. Incorporation of camptothecin in the hydrophobic and acidic environment of SLN matrix was chosen...... to stabilise the lactone ring, which is essential for its antitumour activity, and for avoiding premature loss of drug on the way to target camptothecin to the brain. A multivariate approach was used to assess the influence of the qualitative and quantitative composition on the physicochemical properties...

  6. Effects of a compound from the group of substituted thiadiazines with hypothermia inducing properties on brain metabolism in rats, a study in vivo and in vitro.

    Directory of Open Access Journals (Sweden)

    O B Shevelev

    Full Text Available The aim of the present study was to examine how administration of a compound of 1,3,4- thiadiazine class 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17 with hypothermia inducing properties affects the brain metabolism. The mechanism by which L-17 induces hypothermia is unknown; it may involve hypothalamic central thermoregulation as well as act via inhibition of energy metabolism. We tested the hypothesis that L-17 may induce hypothermia by directly inhibiting energy metabolism. The study in vivo was carried out on Sprague-Dawley adult rats. Two doses of L-17 were administered (190 mg/kg and 760 mg/kg. Brain metabolites were analyzed in control and treated groups using magnetic resonance spectroscopy, along with blood flow rate measurements in carotid arteries and body temperature measurements. Further in vitro studies on primary cultures from rat hippocampus were carried out to perform a mitochondria function test of L-17 pre-incubation (100 μM, 30 min. Analysis of brain metabolites showed no significant changes in 190 mg/kg treated group along with a significant reduction in body temperature by 1.5°C. However, administration of L-17 in higher dose 760 mg/kg provoked changes in brain metabolites indicative of neurotoxicity as well as reduction in carotid arteries flow rate. In addition, a balance change of excitatory and inhibitory neurotransmitters was observed. The L-17 pre-incubation with cell primary cultures from rat brain showed no significant changes in mitochondrial function. The results obtained in the study indicate that acute administration of L-17 190 mg/kg in rats induces mild hypothermia with no adverse effects onto brain metabolism.

  7. In vivo fate of a behaviorally potent ACTH 4-9 analog; evidence for its specific uptake in the brain septal area

    International Nuclear Information System (INIS)

    Verhoef, J.

    1977-01-01

    The effects of ACTH-like neuropeptides on conditioned avoidance behavior and their tentative central sites of action are reviewed. The in vivo fate of the [ 3 H]-ACTH 4-9 analog after various routes of peripheral administration in mice and rats are described, in particular, the uptake of intact peptide in the brain is emphasized, since ACTH-like neuropeptides elicit their behavioral activities by directly affecting the central nervous system. Subsequently, the metabolic profiles of the ACTH 4-9 analog in plasma and brain tissue are reported. The distribution of the [ 3 H]-ACTH 4-9 analog throughout the rat brain is studied after intraventricular injection to allow detection in small brain areas and nuclei and to limit (peripheral) proteolysis. Finally, the effects of increased and decreased circulating levels of both ACTH-like peptides and structurally non-related but behaviorally active neuropeptides on the central distribution profile of intraventricularly injected [ 3 H]-ACTH 4-9 analog are reviewed

  8. Magnetic resonance spectroscopy and metabolism. Applications of proton and sup 13 C NMR to the study of glutamate metabolism in cultured glial cells and human brain in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Portais, J.C.; Pianet, I.; Merle, M.; Raffard, G.; Biran, M.; Labouesse, J.; Canioni, P. (Bordeaux-2 Univ., 33 (FR)); Allard, M.; Kien, P.; Caille, J.M. (Centre Hospitalier Universitaire, 33 Bordeaux (FR))

    1991-01-01

    Nuclear magnetic resonance (NMR) spectroscopy was used to study the metabolism of cells from the central nervous system both in vitro on perchloric acid extracts obtained either from cultured tumoral cells (C6 rat glioma) or rat astrocytes in primary culture, and in vivo within the human brain. Analysis of carbon 13 NMR spectra of perchloric acid extracts prepared from cultured cells in the presence of NMR (1-{sup 13}C) glucose as substrate allowed determination of the glutamate and glutamine enrichments in both normal and tumoral cells. Preliminary results indicated large changes in the metabolism of these amino acids (and also of aspartate and alanine) in the C6 cell as compared to its normal counterpart. Localized proton NMR spectra of the human brain in vivo were obtained at 1.5 T, in order to evaluate the content of various metabolites, including glutamate, in peritumoral edema from a selected volume of 2 x 2 x 2 cm{sup 3}. N-acetyl aspartate, glutamate, phosphocreatine, creatine, choline and inositol derivative resonances were observed in 15 min spectra. N-acetyl-aspartate was found to be at a lower level in contrast to glutamate which was detected at a higher level in the injured area as compared to the controlateral unaffected side.

  9. Implanted, inductively-coupled, radiofrequency coils fabricated on flexible polymeric material: Application to in vivo rat brain MRI at 7 T

    International Nuclear Information System (INIS)

    Ginefri, J.C.; Poirier-Quinot, M.; Darrasse, L.; Rubin, A.; Tatoulian, M.; Woytasik, M.; Boumezbeur, F.; Djemai, B.; Lethimonnier, F.

    2012-01-01

    Combined with high-field MRI scanners, small implanted coils allow for high resolution imaging with locally improved SNR, as compared to external coils. Small flexible implantable coils dedicated to in vivo MRI of the rat brain at 7 T were developed. Based on the Multi-turn Transmission Line Resonator design, they were fabricated with a Teflon substrate using copper micro-molding process and a specific metal-polymer adhesion treatment. The implanted coils were made biocompatible by Polydimethylsiloxane (PDMS) encapsulation. The use of low loss tangent material achieves low dielectric losses within the substrate and the use of the PDMS layer reduces the parasitic coupling with the surrounding media. An implanted coil was implemented in a 7 T MRI system using inductive coupling and a dedicated external pick-up coil for signal transmission. In vivo images of the rat brain acquired with in plane resolution of (150 μm) 2 thanks to the implanted coil revealed high SNR near the coil, allowing for the visualization of fine cerebral structures. (authors)

  10. Beta-endorphin chimeric peptides: Transport through the blood-brain barrier in vivo and cleavage of disulfide linkage by brain

    International Nuclear Information System (INIS)

    Pardridge, W.M.; Triguero, D.; Buciak, J.L.

    1990-01-01

    Water soluble peptides are normally not transported through the blood-brain barrier (BBB). Chimeric peptides may be transportable through the BBB and are formed by the covalent coupling of a nontransportable peptide to a transportable peptide vector, e.g. cationized albumin, using disulfide-based coupling reagents such as N-succinimidyl 3-[2-pyridyldithio(propionate)] (SPDP). The transcytosis of peptide into brain parenchyma, as opposed to vascular sequestration of blood-borne peptide, was quantified using an internal carotid artery perfusion/capillary depletion method. It is shown that [125I]beta-endorphin is not transported through the BBB, but is rapidly cleaved to free [125I] tyrosine via capillary peptidase. Therefore, chimeric peptide was prepared using [125I] [D-Ala2]beta-endorphin (DABE), owing to the resistance of this analogue to peptidase degradation. The [125I] DABE-cationized albumin chimeric peptide is shown to enter brain parenchyma at a rate comparable to that reported previously for unconjugated cationized albumin. When the [125I] DABE-cationized albumin chimeric peptide was incubated with rat brain homogenate at 37 C, the free [125I] DABE was liberated from the cationized albumin conjugate prior to its subsequent degradation into free [125I] tyrosine. Approximately 50% of the chimeric peptide was cleaved within 60 sec of incubation at 37 C. These studies demonstrate that (1) [125I]beta-endorphin is not transported through the BBB in its unconjugated form, (2) a [125I] DABE-cationized albumin chimeric peptide is transported through the BBB into brain parenchyma at a rate comparable to the unconjugated cationized albumin, and (3) brain contains the necessary disulfide reductases for rapid cleavage of the chimeric peptide into free beta-endorphin and this cleavage occurs before degradation of the [125I] DABE into [125I] tyrosine

  11. Beta-endorphin chimeric peptides: Transport through the blood-brain barrier in vivo and cleavage of disulfide linkage by brain

    Energy Technology Data Exchange (ETDEWEB)

    Pardridge, W.M.; Triguero, D.; Buciak, J.L. (UCLA School of Medicine (USA))

    1990-02-01

    Water soluble peptides are normally not transported through the blood-brain barrier (BBB). Chimeric peptides may be transportable through the BBB and are formed by the covalent coupling of a nontransportable peptide to a transportable peptide vector, e.g. cationized albumin, using disulfide-based coupling reagents such as N-succinimidyl 3-(2-pyridyldithio(propionate)) (SPDP). The transcytosis of peptide into brain parenchyma, as opposed to vascular sequestration of blood-borne peptide, was quantified using an internal carotid artery perfusion/capillary depletion method. It is shown that (125I)beta-endorphin is not transported through the BBB, but is rapidly cleaved to free (125I) tyrosine via capillary peptidase. Therefore, chimeric peptide was prepared using (125I) (D-Ala2)beta-endorphin (DABE), owing to the resistance of this analogue to peptidase degradation. The (125I) DABE-cationized albumin chimeric peptide is shown to enter brain parenchyma at a rate comparable to that reported previously for unconjugated cationized albumin. When the (125I) DABE-cationized albumin chimeric peptide was incubated with rat brain homogenate at 37 C, the free (125I) DABE was liberated from the cationized albumin conjugate prior to its subsequent degradation into free (125I) tyrosine. Approximately 50% of the chimeric peptide was cleaved within 60 sec of incubation at 37 C. These studies demonstrate that (1) (125I)beta-endorphin is not transported through the BBB in its unconjugated form, (2) a (125I) DABE-cationized albumin chimeric peptide is transported through the BBB into brain parenchyma at a rate comparable to the unconjugated cationized albumin, and (3) brain contains the necessary disulfide reductases for rapid cleavage of the chimeric peptide into free beta-endorphin and this cleavage occurs before degradation of the (125I) DABE into (125I) tyrosine.

  12. Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

    OpenAIRE

    Jampilek, Josef; Zaruba, Kamil; Oravec, Michal; Kunes, Martin; Babula, Petr; Ulbrich, Pavel; Brezaniova, Ingrid; Opatrilova, Radka; Triska, Jan; Suchy, Pavel

    2015-01-01

    The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics), which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials) by means of an i...

  13. In vivo High Angular Resolution Diffusion-Weighted Imaging of Mouse Brain at 16.4 Tesla

    OpenAIRE

    Alomair, Othman I.; Brereton, Ian M.; Smith, Maree T.; Galloway, Graham J.; Kurniawan, Nyoman D.

    2015-01-01

    Magnetic Resonance Imaging (MRI) of the rodent brain at ultra-high magnetic fields (> 9.4 Tesla) offers a higher signal-to-noise ratio that can be exploited to reduce image acquisition time or provide higher spatial resolution. However, significant challenges are presented due to a combination of longer T 1 and shorter T 2/T2* relaxation times and increased sensitivity to magnetic susceptibility resulting in severe local-field inhomogeneity artefacts from air pockets and bone/brain interfaces...

  14. Radioligands for brain 5-HT{sub 2} receptor imaging in vivo: why do we need them?

    Energy Technology Data Exchange (ETDEWEB)

    Busatto, G.F. [Section of Clinical Neuropharmacology, Dept. of Psychological Medicine, Inst. of Psychiatry, London (United Kingdom)

    1996-08-01

    Recently, PET and SPET radiotracers with high specificity for 5-HT{sub 2} receptors have been developed. These have been studied in baboons and humans with promising results, displaying a binding profile compatible with the brain distribution of 5-HT{sub 2} receptors. It is predicted that studies with the newly developed 5-HT radioligands will substantially increase knowledge about the pharmacology of brain disorders. (orig./MG)

  15. 1H-MR spectroscopy of the rat hippocampus after whole brain irradiation: an in vivo study

    International Nuclear Information System (INIS)

    Ding Weijun; Yang Haihua; Wang Xufeng; Hu Wei; Lei Hao; Li Chunxia; Fang Fang; Fang Zhouxi

    2008-01-01

    Objective: To study the relationships between dynamic changes of the hippocampus metabolites, cognitive impairment and ultrastructural changes of hippocampus in rats during the initial 4 weeks after 6 MV X-ray whole-brain irradiation. Methods: 65 rats were randomly divided into foul groups as sham control (n=5), 10 Gy, 20 Gy and 30 Gy groups (n=20). The learning and memory ability was measured with the Y maze test 4, 8 weeks, 2, 6 months after irradiation. 1 H-MRS was performed after 2 or 4 weeks' brain irradiation. The ultrastructural changes of the hippocampus were observed by electronic microscope. Results: The learning and memorizing ability of irradiation groups was significantly different from that of control group. Compared with control group, the NAA/Ct and Cho/Cr ratio in the left hippocampus in 10 Gy, 20 Gy and 30 Gy groups at 2 weeks and 4 weeks decreased significantly. Neuronal mitochondria edema, endothelial cells swelling and lamina dissociation in myelin sheath were demonstrated in various degrees by electromicroscope at 4 weeks following whole brain irradiation. Conclusions: 1 H-MRS can be used to non-invasively monitor the metabolic changes, both quantitatively and dynamically, of the irradiated rat brain, 1 H-MRS is superior to MRI in detecting early abnormality of the brain. The NAA/Cr and Cho/Cr ratio in irradiated hippocampus could reflect the severity of the brain injury to some extent. (authors)

  16. Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

    Science.gov (United States)

    Wu, Shih-Ying; Sanchez, Carlos Sierra; Samiotaki, Gesthimani; Buch, Amanda; Ferrera, Vincent P.; Konofagou, Elisa E.

    2016-11-01

    Focused ultrasound with microbubbles has been used to noninvasively and selectively deliver pharmacological agents across the blood-brain barrier (BBB) for treating brain diseases. Acoustic cavitation monitoring could serve as an on-line tool to assess and control the treatment. While it demonstrated a strong correlation in small animals, its translation to primates remains in question due to the anatomically different and highly heterogeneous brain structures with gray and white matteras well as dense vasculature. In addition, the drug delivery efficiency and the BBB opening volume have never been shown to be predictable through cavitation monitoring in primates. This study aimed at determining how cavitation activity is correlated with the amount and concentration of gadolinium delivered through the BBB and its associated delivery efficiency as well as the BBB opening volume in non-human primates. Another important finding entails the effect of heterogeneous brain anatomy and vasculature of a primate brain, i.e., presence of large cerebral vessels, gray and white matter that will also affect the cavitation activity associated with variation of BBB opening in different tissue types, which is not typically observed in small animals. Both these new findings are critical in the primate brain and provide essential information for clinical applications.

  17. An in vivo study of the dopaminergic receptors in the brain of man using 11C-pimozide and positron emission tomography

    International Nuclear Information System (INIS)

    Baron, J.C.; Comar, D.; Crouzel, C.; Mestelan, G.; Zarifian, E.; Loo, H.; Agid, Y.

    1982-09-01

    Positron emission tomography was used to establish the regional cerebral pharmacokinetics of a carbon 11-labelled neuroleptic, pimozide, in an attempt to observe its specific bonding to dopaminergic receptors in vivo. The 11 C-pimozide kinetics were compared in two brain structures at the two ends of the dopaminergic receptor density scale: the striatum and cerebellum, very rich in and devoid of these receptors respectively. In 8 patients a significant radioactivity uptake was observed in the striatum as compared with the cerebellum, in agreement with in vivo studies on animals using tritiated pimozide. In 5 patients pre-treated by a therapeutic dose of a cold neuroleptic (haloperidol) this difference in kinetics no longer existed. Moreover no kinetic difference is observed, either before or after haloperidol administration, between the frontal cortex (relatively low in dopaminergic receptors) and cerebellum. These results strongly suggest that pharmacokinetic phenomena directly related to the specific bonding of 11 C-pimozide on the striatal dopaminergic receptors are observable on man in vivo. This specific bonding however remains quantitatively weak as compared with the strong non-specific bonding

  18. 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements

    DEFF Research Database (Denmark)

    Ettrup, Anders; Mikkelsen, Jens D; Lehel, Szabolcs

    2011-01-01

    Small-molecule α(7) nicotinic acetylcholine receptor (α(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α(7)nAChR PET tracer would be important for in vivo quantification of α(7)nAChR bind......Small-molecule α(7) nicotinic acetylcholine receptor (α(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α(7)nAChR PET tracer would be important for in vivo quantification of α(7)n...

  19. 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements

    DEFF Research Database (Denmark)

    Ettrup, Anders; Mikkelsen, Jens D; Lehel, Szabolcs

    2011-01-01

    Small-molecule a(7) nicotinic acetylcholine receptor (a(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled a(7)nAChR PET tracer would be important for in vivo quantification of a(7)nAChR bind......Small-molecule a(7) nicotinic acetylcholine receptor (a(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled a(7)nAChR PET tracer would be important for in vivo quantification of a(7)n...

  20. In vivo carbon-edited detection with proton echo-planar spectroscopic imaging (ICED PEPSI): [3,4-(13)CH(2)]glutamate/glutamine tomography in rat brain.

    Science.gov (United States)

    Hyder, F; Renken, R; Rothman, D L

    1999-12-01

    A method for in vivo carbon-edited detection with proton echo-planar spectroscopic imaging (ICED PEPSI) is described. This method is composed of an echo-planar based acquisition implemented with (13)C-(1)H J editing spectroscopy and is intended for high temporal and spatial resolution in vivo spectroscopic imaging of (13)C turnover, from D-[1,6-(13)C]glucose to glutamate and glutamine, in the brain. At a static magnetic field strength of 7 T, both in vitro and in vivo chemical shift imaging data are presented with a spatial resolution of 8 microL (i.e., 1.25 x 1.25 x 5.00 mm(3)) and a maximum spectral bandwidth of 5.2 ppm in (1)H. Chemical shift imaging data acquired every 11 minutes allowed detection of regional [4-(13)CH(2)]glutamate turnover in rat brain. The [4-(13)CH(2)]glutamate turnover curves, which can be converted to tricarboxylic acid cycle fluxes, showed that the tricarboxylic acid cycle flux (V(TCA)) in pure gray and white matter can range from 1.2 +/- 0.2 to 0.5 +/- 0.1 micromol/g/min, respectively, for morphine-anesthetized rats. The mean cortical V(TCA) from 32 voxels of 1.0 +/- 0.3 micromol/g/min (N = 3) is in excellent agreement with previous localized measurements that have demonstrated that V(TCA) can range from 0.9-1.1 micromol/g/min under identical anesthetized conditions. Magn Reson Med 42:997-1003, 1999. Copyright 1999 Wiley-Liss, Inc.

  1. Brain redox imaging in the pentylenetetrazole (PTZ)-induced kindling model of epilepsy by using in vivo electron paramagnetic resonance and a nitroxide imaging probe.

    Science.gov (United States)

    Emoto, Miho C; Yamato, Mayumi; Sato-Akaba, Hideo; Yamada, Ken-ichi; Fujii, Hirotada G

    2015-11-03

    Much evidence supports the idea that oxidative stress is involved in the pathogenesis of epilepsy, and therapeutic interventions with antioxidants are expected as adjunct antiepileptic therapy. The aims of this study were to non-invasively obtain spatially resolved redox data from control and pentylenetetrazole (PTZ)-induced kindled mouse brains by electron paramagnetic resonance (EPR) imaging and to visualize the brain regions that are sensitive to oxidative damage. After infusion of the redox-sensitive imaging probe 3-methoxycarbonyl-2,2,5,5-tetramethyl-piperidine-1-oxyl (MCP), a series of EPR images of PTZ-induced mouse heads were measured. Based on the pharmacokinetics of the reduction reaction of MCP in the mouse heads, the pixel-based rate constant of its reduction reaction was calculated as an index of redox status in vivo and mapped as a redox map. The obtained redox map showed heterogeneity in the redox status in PTZ-induced mouse brains compared with control. The co-registered image of the redox map and magnetic resonance imaging (MRI) for both control and PTZ-induced mice showed a clear change in the redox status around the hippocampus after PTZ. To examine the role of antioxidants on the brain redox status, the levels of antioxidants were measured in brain tissues of control and PTZ-induced mice. Significantly lower concentrations of glutathione in the hippocampus of PTZ-kindled mice were detected compared with control. From the results of both EPR imaging and the biochemical assay, the hippocampus was found to be susceptible to oxidative damage in the PTZ-induced animal model of epilepsy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Macro- and microelements in the rat liver, kidneys, and brain tissues; sex differences and effect of blood removal by perfusion in vivo.

    Science.gov (United States)

    Orct, Tatjana; Jurasović, Jasna; Micek, Vedran; Karaica, Dean; Sabolić, Ivan

    2017-03-01

    Concentrations of macro- and microelements in animal organs indicate the animal health status and represent reference data for animal experiments. Their levels in blood and tissues could be different between sexes, and could be different with and without blood in tissues. To test these hypotheses, in adult female and male rats the concentrations of various elements were measured in whole blood, blood plasma, and tissues from blood-containing (nonperfused) and blood-free liver, kidneys, and brain (perfused in vivo with an elements-free buffer). In these samples, 6 macroelements (Na, Mg, P, S, K, Ca) and 14 microelements (Fe, Mn, Co, Cu, Zn, Se, I, As, Cd, Hg, Pb, Li, B, Sr) were determined by inductively coupled plasma mass spectrometry following nitric acid digestion. In blood and plasma, female- or male-dominant sex differences were observed for 6 and 5 elements, respectively. In nonperfused organs, sex differences were observed for 3 (liver, brain) or 9 (kidneys) elements, whereas in perfused organs, similar differences were detected for 9 elements in the liver, 5 in the kidneys, and none in the brain. In females, perfused organs had significantly lower concentrations of 4, 5, and 2, and higher concentrations of 10, 4, and 7 elements, respectively, in the liver, kidneys, and brain. In males, perfusion caused lower concentrations of 4, 7, and 2, and higher concentrations of 1, 1, and 7 elements, respectively, in the liver, kidneys, and brain. Therefore, the residual blood in organs can significantly influence tissue concentrations of various elements and their sex-dependency. Copyright © 2017 Elsevier GmbH. All rights reserved.

  3. A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand

    Directory of Open Access Journals (Sweden)

    Rodrigo Teodoro

    2015-10-01

    Full Text Available Changes in the expression of α7 nicotinic acetylcholine receptors (α7 nAChRs in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as radioactively labelled ligands applicable in positron emission tomography (PET. We report on a series of new ligands for α7 nAChRs designed by the combination of dibenzothiophene dioxide as a novel hydrogen bond acceptor functionality with diazabicyclononane as an established cationic center. To assess the structure-activity relationship (SAR of this new basic structure, we further modified the cationic center systematically by introduction of three different piperazine-based scaffolds. Based on in vitro binding affinity and selectivity, assessed by radioligand displacement studies at different rat and human nAChR subtypes and at the structurally related human 5-HT3 receptor, we selected the compound 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl-2-fluorodibenzo-[b,d]thiophene 5,5-dioxide (10a for radiolabeling and further evaluation in vivo. Radiosynthesis of [18F]10a was optimized and transferred to an automated module. Dynamic PET imaging studies with [18F]10a in piglets and a monkey demonstrated high uptake of radioactivity in the brain, followed by washout and target-region specific accumulation under baseline conditions. Kinetic analysis of [18F]10a in pig was performed using a two-tissue compartment model with arterial-derived input function. Our initial evaluation revealed that the dibenzothiophene-based PET radioligand [18F]10a ([18F]DBT-10 has high potential to provide clinically relevant information about the expression and availability of α7 nAChR in the brain.

  4. In vivo (31) P MRS assessment of intracellular NAD metabolites and NAD(+) /NADH redox state in human brain at 4 T.

    Science.gov (United States)

    Lu, Ming; Zhu, Xiao-Hong; Chen, Wei

    2016-07-01

    NAD(+) and NADH play key roles in cellular respiration. Intracellular redox state defined by the NAD(+) /NADH ratio (RX) reflects the cellular metabolic and physiopathological status. By taking advantage of high/ultrahigh magnetic field strengths, we have recently established a novel in vivo (31) P MRS-based NAD assay for noninvasive and quantitative measurements of intracellular NAD concentrations and redox state in animal and human brains at 16.4 T, 9.4 T and 7 T. To explore its potential for clinical application, in this study we investigated the feasibility of assessing the NAD metabolism and redox state in human brain at a lower field of 4 T by incorporating the (1) H-decoupling technique with the in vivo (31) P NAD assay. The use of (1) H decoupling significantly narrowed the linewidths of NAD and α-ATP resonances, resulting in higher sensitivity and better spectral resolution as compared with the (1) H-coupled (31) P spectrum. These improvements made it possible to reliably quantify cerebral NAD concentrations and RX, consistent with previously reported results obtained from similar age human subjects at 7 T. In summary, this work demonstrates the capability and utility of the (1) H-decoupled (31) P MRS-based NAD assay at lower field strength; thus, it opens new opportunities for studying intracellular NAD metabolism and redox state in human brain at clinical settings. This conclusion is supported by the simulation results, indicating that similar performance and reliability as observed at 4T can be achieved at 3 T with the same signal-to-noise ratio. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  5. The common antitussive agent dextromethorphan protects against hyperoxia-induced cell death in established in vivo and in vitro models of neonatal brain injury.

    Science.gov (United States)

    Posod, A; Pinzer, K; Urbanek, M; Wegleiter, K; Keller, M; Kiechl-Kohlendorfer, U; Griesmaier, E

    2014-08-22

    Preterm infants are prematurely subjected to relatively high oxygen concentrations, even when supplemental oxygen is not administered. There is increasing evidence to show that an excess of oxygen is toxic to the developing brain. Dextromethorphan (DM), a frequently used antitussive agent with pleiotropic mechanisms of action, has been shown to be neuroprotective in various models of central nervous system pathology. Due to its numerous beneficial properties, it might also be able to counteract detrimental effects of a neonatal oxygen insult. The aim of the current study was to evaluate its therapeutic potential in established cell culture and rodent models of hyperoxia-induced neonatal brain injury. For in vitro studies pre- and immature oligodendroglial (OLN-93) cells were subjected to hyperoxic conditions for 48 h after pre-treatment with increasing doses of DM. For in vivo studies 6-day-old Wistar rat pups received a single intraperitoneal injection of DM in two different dosages prior to being exposed to hyperoxia for 24h. Cell viability and caspase-3 activation were assessed as outcome parameters at the end of exposure. DM significantly increased cell viability in immature oligodendroglial cells subjected to hyperoxia. In pre-oligodendroglial cells cell viability was not significantly affected by DM treatment. In vivo caspase-3 activation induced by hyperoxic exposure was significantly lower after administration of DM in gray and white matter areas. In control animals kept under normoxic conditions DM did not significantly influence caspase-3-dependent apoptosis. The present results indicate that DM is a promising and safe treatment strategy for neonatal hyperoxia-induced brain injury that merits further investigation. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. Occupational cancer

    International Nuclear Information System (INIS)

    Alderson, M.

    1986-01-01

    This book aims to review the occurrence and causes of occupational cancer and is aimed at assisting medical and safety staff, management and health and safety representatives. It is presented in the following chapters: 1) Epidemiological method 2) Agents causing occupationally induced cancer, including radiation 3) Occupations associated with risk of cancer 4) Aetiology of cancer 5) Control of occupationally induced cancer, research, prevention, legislation, national and international bodies, control of specific occupational carcinogens, including irradiation. (U.K.)

  7. In vitro and in vivo characterisation of nor-{beta}-CIT: a potential radioligand for visualisation of the serotonin transporter in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Bergstroem, K.A. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden)]|[Kuopio University Hospital, Clinical Physiology, FIN-70210 Kuopio (Finland); Halldin, C. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden); Hall, H. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden); Lundkvist, C. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden); Ginovart, N. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden); Swahn, C.G. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden); Farde, L. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm (Sweden)

    1997-06-10

    Radiolabelled 2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)tropane ({beta}-CIT) has been used in clinical studies for the imaging of dopamine and serotonin transporters with single-photon emission tomography (SPET). 2{beta}-Carbomethoxy-3{beta}-(4-iodophenyl)nortropane (nor-{beta}-CIT) is a des-methyl analogue of {beta}-CIT, which in vitro has tenfold higher affinity (IC{sub 50}=0.36 nM) to the serotonin transporter than {beta}-CIT (IC{sub 50}=4.2 nM). Nor-{beta}-CIT may thus be a useful radioligand for imaging of the serotonin transporter. In the present study iodine-125 and carbon-11 labelled nor-{beta}-CIT were prepared for in vitro autoradiographic studies on post-mortem human brain cryosections and for in vivo positron emission tomography (PET) studies in Cynomolgus monkeys. Whole hemisphere autoradiography with [{sup 125}I]nor-{beta}-CIT demonstrated high binding in the striatum, the thalamus and cortical regions of the human brain. Addition of a high concentration (1 {mu}M) of citalopram inhibited binding in the thalamus and the neocortex, but not in the striatum. In PET studies with [{sup 11}C]nor-{beta}-CIT there was rapid uptake of radioactivity in the monkey brain (6% of injected dose at 15 min) and high accumulation of radioactivity in the striatum, thalamus and neocortex. Thalamus to cerebellum and cortex to cerebellum ratios were 2.5 and 1.8 at 60 min, respectively. The ratios obtained with [{sup 11}C]nor-{beta}-CIT were 20%-40% higher than those previously obtained with [{sup 11}C]{beta}-CIT. Radioactivity in the thalamus and the neocortex but not in the striatum was displaceable with citalopram (5 mg/kg). In conclusion, nor-{beta}-CIT binds to the serotonin transporter in the primate brain in vitro and in vivo and has potential for PET and SPET imaging of the serotonin transporter in human brain. (orig.). With 4 figs.

  8. In vitro and in vivo characterisation of nor-β-CIT: a potential radioligand for visualisation of the serotonin transporter in the brain

    International Nuclear Information System (INIS)

    Bergstroem, K.A.; Halldin, C.; Hall, H.; Lundkvist, C.; Ginovart, N.; Swahn, C.G.; Farde, L.

    1997-01-01

    Radiolabelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) has been used in clinical studies for the imaging of dopamine and serotonin transporters with single-photon emission tomography (SPET). 2β-Carbomethoxy-3β-(4-iodophenyl)nortropane (nor-β-CIT) is a des-methyl analogue of β-CIT, which in vitro has tenfold higher affinity (IC 50 =0.36 nM) to the serotonin transporter than β-CIT (IC 50 =4.2 nM). Nor-β-CIT may thus be a useful radioligand for imaging of the serotonin transporter. In the present study iodine-125 and carbon-11 labelled nor-β-CIT were prepared for in vitro autoradiographic studies on post-mortem human brain cryosections and for in vivo positron emission tomography (PET) studies in Cynomolgus monkeys. Whole hemisphere autoradiography with [ 125 I[nor-β-CIT demonstrated high binding in the striatum, the thalamus and cortical regions of the human brain. Addition of a high concentration (1 μM) of citalopram inhibited binding in the thalamus and the neocortex, but not in the striatum. In PET studies with [ 11 C[nor-β-CIT there was rapid uptake of radioactivity in the monkey brain (6% of injected dose at 15 min) and high accumulation of radioactivity in the striatum, thalamus and neocortex. Thalamus to cerebellum and cortex to cerebellum ratios were 2.5 and 1.8 at 60 min, respectively. The ratios obtained with [ 11 C[nor-β-CIT were 20%-40% higher than those previously obtained with [ 11 C[β-CIT. Radioactivity in the thalamus and the neocortex but not in the striatum was displaceable with citalopram (5 mg/kg). In conclusion, nor-β-CIT binds to the serotonin transporter in the primate brain in vitro and in vivo and has potential for PET and SPET imaging of the serotonin transporter in human brain. (orig.). With 4 figs

  9. A two-stage model for in vivo assessment of brain tumor perfusion and abnormal vascular structure using arterial spin labeling.

    Directory of Open Access Journals (Sweden)

    Patrick W Hales

    Full Text Available The ability to assess brain tumor perfusion and abnormalities in the vascular structure in vivo could provide significant benefits in terms of lesion diagnosis and assessment of treatment response. Arterial spin labeling (ASL has emerged as an increasingly viable methodology for non-invasive assessment of perfusion. Although kinetic models have been developed to describe perfusion in healthy tissue, the dynamic behaviour of the ASL signal in the brain tumor environment has not been extensively studied. We show here that dynamic ASL data acquired in brain tumors displays an increased level of 'biphasic' behaviour, compared to that seen in healthy tissue. A new two-stage model is presented which more accurately describes this behaviour, and provides measurements of perfusion, pre-capillary blood volume fraction and transit time, and capillary bolus arrival time. These biomarkers offer a novel contrast in the tumor and surrounding tissue, and provide a means for measuring tumor perfusion and vascular structural abnormalities in a fully non-invasive manner.

  10. In-Vivo Characterization of Glassy Carbon Micro-Electrode Arrays for Neural Applications and Histological Analysis of the Brain Tissue

    Science.gov (United States)

    Vomero, Maria

    The aim of this work is to fabricate and characterize glassy carbon Microelectrode Arrays (MEAs) for sensing and stimulating neural activity, and conduct histological analysis of the brain tissue after the implant to determine long-term performance. Neural applications often require robust electrical and electrochemical response over a long period of time, and for those applications we propose to replace the commonly used noble metals like platinum, gold and iridium with glassy carbon. We submit that such material has the potential to improve the performances of traditional neural prostheses, thanks to better charge transfer capabilities and higher electrochemical stability. Great interest and attention is given in this work, in particular, to the investigation of tissue response after several weeks of implants in rodents' brain motor cortex and the associated materials degradation. As part of this work, a new set of devices for Electrocorticography (ECoG) has been designed and fabricated to improve durability and quality of the previous generation of devices, designed and manufactured by the same research group in 2014. In-vivo long-term impedance measurements and brain activity recordings were performed to test the functionality of the neural devices. In-vitro electrical characterization of the carbon electrodes, as well as the study of the adhesion mechanisms between glassy carbon and different substrates is also part of the research described in this book.

  11. A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier

    NARCIS (Netherlands)

    Hendrikse, NH; de Vries, EGE; Eriks-Fluks, L; van der Graaf, WTA; Hospers, GAP; Willemsen, ATM; Vaalburg, W; Franssen, EJF

    1999-01-01

    Drug resistance is a major cause of chemotherapy failure in cancer treatment, One reason is the overexpression of the drug efflux pump P-glycoprotein (P-gp), involved in multidrug resistance (MDR), In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp

  12. In vivo continuous and simultaneous monitoring of brain energy substrates with a multiplex amperometric enzyme-based biosensor device

    NARCIS (Netherlands)

    De Lima Braga Lopes Cordeiro, Carlos; de Vries, M.G.; Ngabi, W; Oomen, P.E.; Cremers, T.I.F.H.; Westerink, B.H.C.

    2015-01-01

    Enzyme-based amperometric biosensors are widely used for monitoring key biomarkers. In experimental neuroscience there is a growing interest in in vivo continuous and simultaneous monitoring of metabolism-related biomarkers, like glucose, lactate and pyruvate. The use of multiplex biosensors will

  13. In vivo imaging of brain aromatase in female baboons: [11C]vorozole kinetics and effect of the menstrual cycle.

    Science.gov (United States)

    Pareto, Deborah; Biegon, Anat; Alexoff, David; Carter, Pauline; Shea, Coreen; Muench, Lisa; Xu, Youwen; Fowler, Joanna S; Kim, Sunny W; Logan, Jean

    2013-01-01

    The aim of this work was to quantify the brain distribution of the enzyme aromatase in the female baboon with positron emission tomography and the tracer [11C]vorozole using three different quantification methods for estimating the total distribution volume (V(T)): a graphical method, compartment modeling, and a tissue to plasma ratio. The graphical model and the compartment modeling gave similar estimates to the data and similar values (correlation R  =  .988; p  =  .0001). [11C]Vorozole shows a rapid uptake by the brain followed by a relatively constant accumulation, suggesting the possibility of using the tissue to plasma ratio as an estimate of V(T). The highest uptake of [11C]vorozole in the baboon brain was measured in the amygdala, followed by the preoptic area and hypothalamus, basal ganglia, and cortical areas. Pretreatment studies with vorozole or letrozole showed a generalized decrease in brain accumulation and V(T). The results suggested that the physiologic changes in gonadal hormone levels accompanying the menstrual cycle had a significant effect on brain aromatase V(T).

  14. Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation.

    Science.gov (United States)

    Đorđević, Sanela M; Cekić, Nebojša D; Savić, Miroslav M; Isailović, Tanja M; Ranđelović, Danijela V; Marković, Bojan D; Savić, Saša R; Timić Stamenić, Tamara; Daniels, Rolf; Savić, Snežana D

    2015-09-30

    This paper describes design and evaluation of parenteral lecithin-based nanoemulsions intended for brain delivery of risperidone, a poorly water-soluble psychopharmacological drug. The nanoemulsions were prepared through cold/hot high pressure homogenization and characterized regarding droplet size, polydispersity, surface charge, morphology, drug-vehicle interactions, and physical stability. To estimate the simultaneous influence of nanoemulsion formulation and preparation parameters--co-emulsifier type, aqueous phase type, homogenization temperature--on the critical quality attributes of developed nanoemulsions, a general factorial experimental design was applied. From the established design space and stability data, promising risperidone-loaded nanoemulsions (mean size about 160 nm, size distribution Solutol(®) HS15 as co-emulsifier, were produced by hot homogenization and their ability to improve risperidone delivery to the brain was assessed in rats. Pharmacokinetic study demonstrated erratic brain profiles of risperidone following intraperitoneal administration in selected nanoemulsions, most probably due to their different droplet surface properties (different composition of the stabilizing layer). Namely, polysorbate 80-costabilized nanoemulsion showed increased (1.4-7.4-fold higher) risperidone brain availability compared to other nanoemulsions and drug solution, suggesting this nanoemulsion as a promising carrier worth exploring further for brain targeting. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Nanotoxicity of poly(n-butylcyano-acrylate) nanoparticles at the blood-brain barrier, in human whole blood and in vivo.

    Science.gov (United States)

    Kolter, Marise; Ott, Melanie; Hauer, Christian; Reimold, Isolde; Fricker, Gert

    2015-01-10

    Therapy of diseases of the central nervous system is a major challenge since drugs have to overcome the blood-brain barrier (BBB). A powerful strategy to enhance cerebral drug concentration is administration of drug-loaded poly(n-butylcyano-acrylate) (PBCA) nanoparticles coated with polysorbate 80 (PS80). This study evaluates the toxicity of PBCA-nanoparticles at the BBB, representing the target organ, the inflammatory response in human whole blood, as the site of administration and in a rat model in vivo. PBCA-nanoparticles were prepared by a mini-emulsion method and characterized concerning size, surface charge, shape and PS80-adsorption. The influence on metabolic activity, cell viability and integrity of the BBB was analyzed in an in vitro model of the BBB. In ex vivo experiments in human whole blood the release of 12 inflammatory cytokines was investigated. In addition, the inflammatory response was studied in vivo in rats and complemented with the analysis of different organ toxicity parameters. PBCA-nanoparticles showed time- and concentration-dependent effects on metabolic activity, cell viability and BBB integrity. No cell death or loss of metabolic activity was observed for nanoparticle-concentrations ≤500μg/ml up to 3h of treatment. Within 12 tested inflammatory cytokines, only interleukin-8 displayed a significant release after nanoparticle exposure in human blood. No severe inflammatory processes or organ damages were identified in rats in vivo. Thus, PBCA-nanoparticles are a promising drug delivery system to overcome the BBB since they showed hardly any cytotoxic or inflammatory effect at therapeutic concentrations and incubation times. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Homing and Tracking of Iron Oxide Labelled Mesenchymal Stem Cells After Infusion in Traumatic Brain Injury Mice: a Longitudinal In Vivo MRI Study.

    Science.gov (United States)

    Mishra, Sushanta Kumar; Khushu, Subash; Singh, Ajay K; Gangenahalli, Gurudutta

    2018-06-17

    Stem cells transplantation has emerged as a promising alternative therapeutic due to its potency at injury site. The need to monitor and non-invasively track the infused stem cells is a significant challenge in the development of regenerative medicine. Thus, in vivo tracking to monitor infused stem cells is especially vital. In this manuscript, we have described an effective in vitro labelling method of MSCs, a serial in vivo tracking of implanted stem cells at traumatic brain injury (TBI) site through 7 T magnetic resonance imaging (MRI). Proper homing of infused MSCs was carried out at different time points using histological analysis and Prussian blue staining. Longitudinal in vivo tracking of infused MSCs were performed up to 21 days in different groups through MRI using relaxometry technique. Results demonstrated that MSCs incubated with iron oxide-poly-L-lysine complex (IO-PLL) at a ratio of 50:1.5 μg/ml and a time period of 6 h was optimised to increase labelling efficiency. T2*-weighted images and relaxation study demonstrated a significant signal loss and effective decrease in transverse relaxation time on day-3 at injury site after systemic transplantation, revealed maximum number of stem cells homing to the lesion area. MRI results further correlate with histological and Prussian blue staining in different time periods. Decrease in negative signal and increase in relaxation times were observed after day-14, may indicate damage tissue replacement with healthy tissue. MSCs tracking with synthesized negative contrast agent represent a great advantage during both in vitro and in vivo analysis. The proposed absolute bias correction based relaxometry analysis could be extrapolated for stem cell tracking and therapies in various neurodegenerative diseases.

  17. Effect of thiamine deficiency, pyrithiamine and oxythiamine on pyruvate metabolism in rat liver and brain in vivo

    International Nuclear Information System (INIS)

    Meghal, S.K.; O'Neal, R.M.; Koeppe, R.E.

    1977-01-01

    Rats were fed either a thiamine-deficient diet or diets containing pyrithiamine or oxythiamine. When symptoms of thiamine deficiency appeared, the animals were injected intraperitoneally with [2- 14 C] pyruvate six to twelve minutes prior to sacrifice. Free glutamic and aspartic acids were isolated from liver and brain and degraded. The results indicate that, in thiamine-deficient or oxythiamine-treated rats, pyruvate metabolism in liver and brain is similar to that in normal animals. In contrast, pyrithinamine drastically decreases the oxidative decarboxylation of pyruvate by rat liver. (auth.)

  18. BDNF Val66met and 5-HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels

    DEFF Research Database (Denmark)

    Fisher, Patrick M; Holst, Klaus K; Adamsen, Dea

    2015-01-01

    ) polymorphism. We applied a linear latent variable model (LVM) using regional 5-HT4 binding values (neocortex, amygdala, caudate, hippocampus, and putamen) from 68 healthy humans, allowing us to explicitly model brain-wide and region-specific genotype effects on 5-HT4 binding. Our data supported an LVM wherein...... specifically affects 5-HT4 binding in the neocortex. These findings implicate serotonin signaling as an important molecular mediator underlying the effects of BDNF val66met and 5-HTTLPR on behavior and related risk for neuropsychiatric illness in humans. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc....

  19. In vivo formation of natural HgSe nanoparticles in the liver and brain of pilot whales

    DEFF Research Database (Denmark)

    Gajdosechova, Z.; Lawan, M. M.; Urgast, D. S.

    2016-01-01

    Se) nanoparticles in the liver and brain of long-finned pilot whales are attached to Se-rich structures and possibly act as a nucleation point for the formation of large Se-Hg clusters, which can grow with age to over 5 μm in size. The detoxification mechanism is fully developed from the early age of the animals...

  20. The formulation, characterization and in vivo evaluation of a magnetic carrier for brain delivery of NIR dye

    Energy Technology Data Exchange (ETDEWEB)

    Raut, S L; Kirthivasan, B; Bommana, M M; Squillante, E; Sadoqi, M, E-mail: squillae@stjohns.edu, E-mail: sadoqim@stjohns.edu [College of Pharmacy and Allied Health Professions, St John' s University, Queens, NY 11439 (United States)

    2010-10-01

    This work reports the targeting of the near infrared (NIR) dye indocyanine green (ICG) to the brain using composite nanoparticles. Thermal decomposition of iron pentacarbonyl was used to synthesize monodisperse oleic acid coated magnetic nanoparticles (OAMNP). Synthesized OAMNP and ICG were encapsulated in a poly (lactide-co-glycolide) matrix using an emulsion evaporation method. Different batches containing OAMNP:PLGA ratios (1:4, 1:2 and 3:4) were prepared with ICG (group B-1, 2, 3) and without ICG (group A-1, 2, 3) loading. All the formulations were characterized in terms of morphology, particle size, zeta potential, magnetic content, ICG encapsulation efficiency and the spectral properties of ICG. The optimized formulation showed an encapsulation efficiency of 56 {+-} 4.6% for ICG and 57 {+-} 1.37% for OAMNP. The biodistribution and brain targeting study involved three groups of six animals, each with 0.4 mg kg{sup -1} equivalent of ICG, given as neat ICG solution, composite nanoparticles without the aid of a magnetic field, and composite nanoparticles under the influence of a magnetic field (8000 G) to groups 1, 2 and 3 respectively. The tissue analysis and microscopy images revealed a significantly higher brain concentration of ICG (p < 0.05) for group 3 than the two control groups. These results are encouraging for the brain delivery of hydrophilic dyes/drugs using this method for biomedical applications.

  1. A transgenic zebrafish model for the in vivo study of the blood and choroid plexus brain barriers using claudin 5

    Directory of Open Access Journals (Sweden)

    Lisanne Martine van Leeuwen

    2018-02-01

    Full Text Available The central nervous system (CNS has specific barriers that protect the brain from potential threats and tightly regulate molecular transport. Despite the critical functions of the CNS barriers, the mechanisms underlying their development and function are not well understood, and there are very limited experimental models for their study. Claudin 5 is a tight junction protein required for blood brain barrier (BBB and, probably, choroid plexus (CP structure and function in vertebrates. Here, we show that the gene claudin 5a is the zebrafish orthologue with high fidelity expression, in the BBB and CP barriers, that demonstrates the conservation of the BBB and CP between humans and zebrafish. Expression of claudin 5a correlates with developmental tightening of the BBB and is restricted to a subset of the brain vasculature clearly delineating the BBB. We show that claudin 5a-expressing cells of the CP are ciliated ependymal cells that drive fluid flow in the brain ventricles. Finally, we find that CP development precedes BBB development and that claudin 5a expression occurs simultaneously with angiogenesis. Thus, our novel transgenic zebrafish represents an ideal model to study CNS barrier development and function, critical in understanding the mechanisms underlying CNS barrier function in health and disease.

  2. Comparison of different pulse sequences for in vivo determination of T1 relaxation times in the human brain

    DEFF Research Database (Denmark)

    Kjaer, L; Henriksen, O

    1988-01-01

    ). T1 measurements were performed on the human brain using a whole body MR scanner operating at 1.5 tesla. Three different pulse sequences were compared including two 6-points inversion recovery (IR) sequences with TR = 2.0 s and 4.0, respectively, and a 12-points partial saturation inversion recovery...

  3. The development of in vivo tracer methods to obtain new information about human disease: a study of the hallucinating brain

    International Nuclear Information System (INIS)

    Jones, T.; Silbersweig, D.A.; Stern, E.; Schnorr, L.; Seaward, J.; Clark, J.C.; Lammertsma, A.A.; Grootoonk, S.

    1996-01-01

    An outline is provided of the development of methodological strategies to address the question of focal cerebral activation during hallucinations in schizophrenic patients. In so doing, the innovation and diligence required to tailor in vivo tracer procedures to specific clinical research issues are highlighted. Attention is drawn to the complexity of methodological advances and the way in which they are based upon close scientific and technical collaboration between clinical scientists, and non-clinical scientists and research support staff. (orig.). With 1 fig

  4. Intranasal haloperidol-loaded miniemulsions for brain targeting: Evaluation of locomotor suppression and in-vivo biodistribution.

    Science.gov (United States)

    El-Setouhy, Doaa Ahmed; Ibrahim, A B; Amin, Maha M; Khowessah, Omneya M; Elzanfaly, Eman S

    2016-09-20

    Haloperidol is a commonly prescribed antipsychotic drug currently administered as oral and injectable preparations. This study aimed to prepare haloperidol intranasal miniemulsion helpful for psychiatric emergencies and exhibiting lower systemic exposure and side effects associated with non-target site delivery. Haloperidol miniemulsions were successfully prepared by spontaneous emulsification adopting 2(3) factorial design. The effect of three independent variables at two levels each namely; oil type (Capmul®-Capryol™90), lipophilic emulsifier type (Span 20-Span 80) and HLB value (12-14) on globule size, PDI and percent locomotor activity inhibition in mice was evaluated. The optimized formula (F4, Capmul®, Tween 80/Span 20, HLB 14) showed globule size of 209.5±0.98nm, PDI of 0.402±0.03 and locomotor inhibition of 83.89±9.15% with desirability of 0.907. Biodistribution study following intranasal and intravenous administration of the radiolabeled (99m)Tc mucoadhesive F4 revealed that intranasal administration achieved 1.72-fold higher and 6 times faster peak brain levels compared with intravenous administration. Drug targeting efficiency percent and brain/blood exposure ratios remained above 100% and 1 respectively after intranasal instillation compared to a maximum brain/blood exposure ratio of 0.8 post intravenous route. Results suggested the CNS delivery of major fraction of haloperidol via direct transnasal to brain pathway that can be a promising alternative to oral and parenteral routes in chronic and acute situations. Haloperidol concentration of 275.6ng/g brain 8h post intranasal instillation, higher than therapeutic concentration range of haloperidol (0.8 to 5.15ng/ml), suggests possible sustained delivery of the drug through nasal route. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Additive effects of levonorgestrel and ethinylestradiol on brain aromatase (cyp19a1b) in zebrafish specific in vitro and in vivo bioassays

    Energy Technology Data Exchange (ETDEWEB)

    Hinfray, N., E-mail: nathalie.hinfray@ineris.fr [INERIS, Unité d' écotoxicologie in vitro et in vivo , Verneuil-en-Halatte (France); Tebby, C. [INERIS, Unité Modèles pour l' Ecotoxicologie et la Toxicologie, Verneuil-en-Halatte (France); Garoche, C.; Piccini, B. [INERIS, Unité d' écotoxicologie in vitro et in vivo , Verneuil-en-Halatte (France); Bourgine, G. [IRSET, équipe NEED, Université de Rennes 1, Rennes (France); Aït-Aïssa, S. [INERIS, Unité d' écotoxicologie in vitro et in vivo , Verneuil-en-Halatte (France); Kah, O. [IRSET, équipe NEED, Université de Rennes 1, Rennes (France); Pakdel, F. [IRSET, Inserm U1085, équipe TREC, Université de Rennes 1, Rennes (France); Brion, F. [INERIS, Unité d' écotoxicologie in vitro et in vivo , Verneuil-en-Halatte (France)

    2016-09-15

    Estrogens and progestins are widely used in combination in human medicine and both are present in aquatic environment. Despite the joint exposure of aquatic wildlife to estrogens and progestins, very little information is available on their combined effects. In the present study we investigated the effect of ethinylestradiol (EE2) and Levonorgestrel (LNG), alone and in mixtures, on the expression of the brain specific ER-regulated cyp19a1b gene. For that purpose, recently established zebrafish-derived tools were used: (i) an in vitro transient reporter gene assay in a human glial cell line (U251-MG) co-transfected with zebrafish estrogen receptors (zfERs) and the luciferase gene under the control of the zebrafish cyp19a1b gene promoter and (ii) an in vivo bioassay using a transgenic zebrafish expressing GFP under the control of the zebrafish cyp19a1b gene promoter (cyp19a1b-GFP). Concentration-response relationships for single chemicals were modeled and used to design the mixture experiments following a ray design. The results from mixture experiments were analyzed to predict joint effects according to concentration addition and statistical approaches were used to characterize the potential interactions between the components of the mixtures (synergism/antagonism). We confirmed that some progestins could elicit estrogenic effects in fish brain. In mixtures, EE2 and LNG exerted additive estrogenic effects both in vitro and in vivo, suggesting that some environmental progestin could exert effects that will add to those of environmental (xeno-)estrogens. Moreover, our zebrafish specific assays are valuable tools that could be used in risk assessment for both single chemicals and their mixtures. - Highlights: • Combined effects of EE2 and LNG were assessed on ER-dependent cyp19a1b expression. • EE2 and LNG alone induced brain aromatase in zebrafish specific bioassays. • Experimental ray design allowed complete concentration-response surfaces modeling. • EE2 and

  6. Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy.

    Directory of Open Access Journals (Sweden)

    Julius O Enoru

    Full Text Available Parkinson's disease (PD is a neurodegenerative aging disorder in which postmortem PD brain exhibits neuroinflammation, as well as synucleinopathy-associated protein phosphatase 2A (PP2A enzymatic activity loss. Based on our translational research, we began evaluating the PD-repurposing-potential of an anti-inflammatory, neuroprotective, and PP2A stimulatory oral drug that is FDA-approved for multiple sclerosis, FTY720 (fingolimod, Gilenya®. We also designed two new FTY720 analogues, FTY720-C2 and FTY720-Mitoxy, with modifications that affect drug potency and mitochondrial localization, respectively. Herein, we describe the metabolic stability and metabolic profiling of FTY720-C2 and FTY720-Mitoxy in liver microsomes and hepatocytes. Using mouse, rat, dog, monkey, and human liver microsomes the intrinsic clearance of FTY720-C2 was 22.5, 79.5, 6.0, 20.2 and 18.3 μL/min/mg; and for FTY720-Mitoxy was 1.8, 7.8, 1.4, 135.0 and 17.5 μL/min/mg, respectively. In hepatocytes, both FTY720-C2 and FTY720-Mitoxy were metabolized from the octyl side chain, generating a series of carboxylic acids similar to the parent FTY720, but without phosphorylated metabolites. To assess absorption and distribution, we gave equivalent single intravenous (IV or oral doses of FTY720-C2 or FTY720-Mitoxy to C57BL/6 mice, with two mice per time point evaluated. After IV delivery, both FTY720-C2 and FTY720-Mitoxy were rapidly detected in plasma and brain; and reached peak concentrations at the first sampling time points. After oral dosing, FTY720-C2 was present in plasma and brain, although FTY720-Mitoxy was not orally bioavailable. Brain-to-plasma ratio of both compounds increased time-dependently, suggesting a preferential partitioning to the brain. PP2A activity in mouse adrenal gland increased ~2-fold after FTY720-C2 or FTY720-Mitoxy, as compared to untreated controls. In summary, FTY720-C2 and FTY720-Mitoxy both (i crossed the blood-brain-barrier; (ii produced metabolites

  7. Regional in vivo binding of (/sup 3/H)N-propylnorapomorphine in the mouse brain. Evidence for labelling of central dopamine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Koehler, C; Fuxe, K; Ross, S B [Astra Pharmaceuticals AB, Soedertaelje (Sweden)

    1981-07-10

    Tail vein injections of (/sup 3/H)N-propylnorapomorphine ((/sup 3/H)NPA) in male mice resulted in a dose-related accumulation of radioactivity in the following brain regions: striatum (max), olfactory tubercle and cerebellum (min). The specific binding was saturable with increasing concentrations of the drug and stereospecifically displaced by (+)butaclamol. Dopamine agonists (apomorphine, NPA and bromocriptine) and antagonists (spiperone, haloperidol, (+)butaclamol and l-sulpiride) all caused dose-dependent prevention of (/sup 3/H)NPA binding. Mianserin, phenoxybenzamine and propranolol did not prevent the in vivo (/sup 3/H)NPA binding suggesting that (/sup 3/H)NPA binds specifically to dopamine receptors in the striatum and the olfactory tubercle of the mouse.

  8. Quantification of [11C]yohimbine binding to α2 adrenoceptors in rat brain in vivo

    DEFF Research Database (Denmark)

    Phan, Jenny-Ann; Landau, Anne M.; Wong, Dean F.

    2015-01-01

    We quantified the binding potentials (BPND) of [11C]yohimbine binding in rat brain to alpha-2 adrenoceptors to evaluate [11C]yohimbine as an in vivo marker of noradrenergic neurotransmission and to examine its sensitivity to the level of noradrenaline. Dual [11C]yohimbine dynamic positron emissio...... is sensitive to a challenge known to increase the extracellular level of noradrenaline, which can benefit future PET investigations of pathologic conditions related to disrupted noradrenergic neurotransmission....... challenge with amphetamine induced a significant decline of [11C]yohimbine BPND of ∼38% in all volumes of interest. The BPND was greatest in the thalamus and striatum, followed in descending order by, frontal cortex, pons, and cerebellum. The experimental data demonstrate that [11C]yohimbine binding...

  9. Quantitative NMR proton spectroscopy in vivo at 1,5 Tesla and possible applications to investigations of brain metabolism of depressive patients

    International Nuclear Information System (INIS)

    Metzler, D.

    1997-12-01

    Using a clinical magnetic resonance imaging/spectroscopy system 22 patients suffering from bipolar disorders and 22 healthy volunteers were examined by localized in vivo proton spectroscopy. The measurements were performed on a 1.5 Tesla whole body scanner of Siemens AG, Magnetom SP 4000, using the standard head coil (CP). For localization a STEAM sequence was used with an echo times TE of 55 ms. A recovery time of 3500 ms was chosen. The number of acquisitions was 256. The spectra were acquired from voxel volumes of 20 x 30 x 20 mm 3 . Three Gaussian presaturation pulses (CHESS) with subsequent dephasing gradients were used for water suppression. After correction for eddy-current effects and Fast-Fourier transformation the intensities of myo-inositol, choline compounds, creatine together with phospho-creatine, and N-acetylaspartate were evaluated from the spectra. The spectra from the frontal brain of depressed patients and controls revealed mInos/Cr ratios of about 0,4 - 0,5. This lies within the range, which is presumed to be the mInos concentration in 1 H-Magnetic Resonance Spectroscopy studies in human brain in vivo. Concerning the total sample (N = 2 x 22) there were no intergroup differences in the present study. Concluding a subsample of subjects younger than 40 years (N = 2 x 10), depressives showed lower mInos levels than controls in the right frontal lobe. The patients showed a significant positive correlation between age and mInos/Cr in the right frontal lobe, while in the left frontal lobe this could be seen only as a trend. In contrast, NAA/Cr decreased with increasing age. There were neither significant differences between sex nor between hemispheres. (author)

  10. A hybrid clinical-research depth electrode for acute and chronic in vivo microelectrode recording of human brain neurons. Technical note.

    Science.gov (United States)

    Howard, M A; Volkov, I O; Granner, M A; Damasio, H M; Ollendieck, M C; Bakken, H E

    1996-01-01

    For several decades, important scientific information has been gained from in vivo microelectrode recordings of individual human cerebral cortical neurons in patients with epilepsy. The experimental methods used, however, are technically complex and require a highly skilled intraoperative team. There are also significant experimental time limitations, as well as constraints on the type of behavioral tests conducted, and the brain regions that may be safely studied. In this report, a new method is described for obtaining in vivo microelectrode recordings using a hybrid depth electrode (HDE). High-impedance research recording contacts are interspersed between low-impedance clinical electroencephalographic (EEG) contacts along the HDE shaft. The HDE has the same external physical properties as a standard clinical depth electrode (DE). Following preclinical laboratory testing, 15 HDEs were used in the evaluation of six patients with medically refractory epilepsy. High-quality EEG recordings were obtained in all cases (two acute intraoperative, four from the chronic epilepsy monitoring unit). Action potentials from individual neurons were successfully recorded during all experimental sessions; however, the chronic preparations were clearly superior. Chronic HDEs are placed using a standard stereotactic system, and the locations of recording contacts are documented on a postimplantation imaging study. The quality of the chronic research recordings was excellent over study periods ranging from 5 to 14 days. The patients rested comfortably on the ward and were able to cooperate with complex experimental instructions. Basic neuroscientists participated fully in all aspects of the chronic investigations. The use of an HDE in place of a standard clinical DE may now allow detailed physiological investigations of any brain region targeted for clinical DE implantation.

  11. Coronal in vivo forward-imaging of rat brain morphology with an ultra-small optical coherence tomography fiber probe

    Science.gov (United States)

    Xie, Yijing; Bonin, Tim; Löffler, Susanne; Hüttmann, Gereon; Tronnier, Volker; Hofmann, Ulrich G.

    2013-02-01

    A well-established navigation method is one of the key conditions for successful brain surgery: it should be accurate, safe and online operable. Recent research shows that optical coherence tomography (OCT) is a potential solution for this application by providing a high resolution and small probe dimension. In this study a fiber-based spectral-domain OCT system utilizing a super-luminescent-diode with the center wavelength of 840 nm providing 14.5 μm axial resolution was used. A composite 125 μm diameter detecting probe with a gradient index (GRIN) fiber fused to a single mode fiber was employed. Signals were reconstructed into grayscale images by horizontally aligning A-scans from the same trajectory with different depths. The reconstructed images can display brain morphology along the entire trajectory. For scans of typical white matter, the signals showed a higher reflection of light intensity with lower penetration depth as well as a steeper attenuation rate compared to the scans typical for gray matter. Micro-structures such as axon bundles (70 μm) in the caudate nucleus are visible in the reconstructed images. This study explores the potential of OCT to be a navigation modality in brain surgery.

  12. In vitro and in vivo evidence for active brain uptake of the GHB analogue HOCPCA by the monocarboxylate transporter subtype 1

    DEFF Research Database (Denmark)

    Thiesen, Louise; Kehler, Jan; Clausen, Rasmus P

    2015-01-01

    and in vivo, and to investigate the hypothesis that HOCPCA, like GHB, is a substrate for the monocarboxylate transporters (MCTs). For in vitro uptake studies, MCT1, 2 and 4 were recombinantly expressed in Xenopus laevis oocytes and the previously reported radioligand [(3)H]HOCPCA was used (as substrate......). HOCPCA inhibited the uptake of the endogenous MCT substrate L-[(14)C]lactate, and [(3)H]HOCPCA was shown to act as substrate for MCT1 and 2 (Km values in the low millimolar range). Introducing single point amino acid mutations into positions essential for MCT function supported that HOCPCA binds...... to the endogenous substrate pocket of MCTs. MCT1-mediated brain entry of HOCPCA (10 mg/kg s.c.) was further confirmed in vivo in mice by co-administration of increasing doses of the MCT inhibitor [(R)-5-(3-hydroxypyrrolidine-1-carbonyl)-1-isobutyl-3-methyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H...

  13. Altered metabolites of the rat hippocampus after mild and moderate traumatic brain injury - a combined in vivo and in vitro 1 H-MRS study.

    Science.gov (United States)

    Singh, Kavita; Trivedi, Richa; Verma, Ajay; D'souza, Maria M; Koundal, Sunil; Rana, Poonam; Baishya, Bikash; Khushu, Subash

    2017-10-01

    Traumatic brain injury (TBI) has been shown to affect hippocampus-associated learning, memory and higher cognitive functions, which may be a consequence of metabolic alterations. Hippocampus-associated disorders may vary depending on the severity of injury [mild TBI (miTBI) and moderate TBI (moTBI)] and time since injury. The underlying hippocampal metabolic irregularities may provide an insight into the pathological process following TBI. In this study, in vivo and in vitro proton magnetic resonance spectroscopy ( 1 H-MRS) data were acquired from the hippocampus region of controls and TBI groups (miTBI and moTBI) at D0 (pre-injury), 4 h, Day 1 and Day 5 post-injury (PI). In vitro MRS results indicated trauma-induced changes in both miTBI and moTBI; however, in vivo MRS showed metabolic alterations in moTBI only. miTBI and moTBI showed elevated levels of osmolytes indicating injury-induced edema. Altered levels of citric acid cycle intermediates, glutamine/glutamate and amino acid metabolism indicated injury-induced aberrant bioenergetics, excitotoxicity and oxidative stress. An overall similar pattern of pathological process was observed in both miTBI and moTBI, with the distinction of depleted N-acetylaspartate levels (indicating neuronal loss) at 4 h and Day 1 and enhanced lactate production (indicating heightened energy depletion leading to the commencement of the anaerobic pathway) at Day 5 in moTBI. To the best of our knowledge, this is the first study to investigate the hippocampus metabolic profile in miTBI and moTBI simultaneously using in vivo and in vitro MRS. Copyright © 2017 John Wiley & Sons, Ltd.

  14. In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PET

    International Nuclear Information System (INIS)

    Conti, Peter S.; Bading, James R.; Mouton, Peter P.; Links, Jonathan M.; Alauddin, Mian M.; Fissekis, John D.; Ravert, Hayden T.; Hilton, John; Wong, Dean F.; Anderson, James H.

    2008-01-01

    Introduction: Noncatabolized thymidine analogs are being developed for use in imaging DNA synthesis. We sought to relate a labeling index measured by immunohistochemical staining bromodeoxyuridine (BUdR) technique to the uptake of 11 C 2'-fluoro-5-methyl-1-β-D-arabinofuranosyluracil (FMAU) measured with positron emission tomography (PET) in a brain tumor model. Methods: Adult beagles (n=8) with implanted brain tumors received [ 11 C]FMAU and dynamic imaging with arterial sampling. Six dogs were then infused with BUdR (200 mg/m 2 ) and sacrificed. Tumor time-activity curves (TACs) obtained from computed-tomography-defined regions of interest were corrected for partial volume effects and crosstalk from brain tissue. Tissue was analyzed for the percentage of tumor volume occupied by viable cells and by viable cells in S-phase as identified by BUdR staining. PET/[ 11 C]FMAU and BUdR were compared by linear regression analysis and analysis of variance, as well as by a nonparametric rank correlation test. Results: Tumor standardized uptake values (SUVs) and tumor-to-contralateral-brain uptake ratios at 50 min were 1.6±0.4 and 5.5±1.2 (n=8; mean±S.E.M.), respectively. No 11 C-labeled metabolites were observed in the blood through 60 min. Tumor TACs were well described with a three-compartment/four-parameter model (k 4 =0) and by Patlak analysis. Parametric statistical analysis showed that FMAU clearance from plasma into tumor Compartment 3 (K FMAU ) was significantly correlated with S-phase percent volume (P=.03), while tumor SUV was significantly correlated with both S-phase percent volume and cell percent volume (P=.02 and .03, respectively). Patlak slope, K FMAU and tumor SUV were equivalent with regard to rank correlation analysis, which showed that tumor uptake and trapping of FMAU were correlated with the volume density of dividing cells (P=.0003) rather than nondividing cells (P=.3). Conclusions: Trapping of [ 11 C]FMAU correlated with tumor growth rate, as

  15. MCNPx computational estimation of the calibration factor of an In vivo counter for {sup 18}F-FDG activity incorporated in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Melo M, B.; Ferreira F, T. C.; Duarte V, K.; Da Silva, T. A. [Centro de Desenvolvimento da Tecnologia Nuclear / CNEN, Av. Pte. Antonio Carlos 6627, 31270-901 Belo Horizonte, Minas Gerais (Brazil); Ribeiro de C, T. P., E-mail: bmm@cdtn.br [Universidade Federal de Minas Gerais, Departamento de Engenharia Nuclear, Programa de Pos-graduacao em Ciencias e Tecnicas, Av. Pte. Antonio Carlos 6627, 31270-901 Belo Horizonte, Minas Gerais (Brazil)

    2016-10-15

    In previous work, the computational modeling of the Centro de Desenvolvimento da Tecnologia Nuclear in vivo counter for estimation of {sup 18}F-FGD activity incorporated into workers brains was validated. Here, we studied the calibration factor (Cf) for seven distinct voxelized computational phantoms including the reference models from ICRP 110. Computational simulations were also carried out to study the effect of increasing the distance between the detector and the brain up to 100 cm. The degree of correlation among geometric and anatomical parameters of the computational models and the calibration factors were also evaluated. The morphological diversity of the computational phantoms resulted Cf variations greater than 38% (39.8 ± 0.2 to 64.6 ± 0.5 Bq.CPS{sup -1}). Despite the variations, Cf has been reduced by the increasing distance, although the remarkable decrease in counting efficiency makes prohibitive this geometry. These findings suggest that head anatomic parameters can be used to improve Cf estimation. (Author)

  16. MCNPx computational estimation of the calibration factor of an In vivo counter for "1"8F-FDG activity incorporated in the brain

    International Nuclear Information System (INIS)

    Melo M, B.; Ferreira F, T. C.; Duarte V, K.; Da Silva, T. A.; Ribeiro de C, T. P.

    2016-10-01

    In previous work, the computational modeling of the Centro de Desenvolvimento da Tecnologia Nuclear in vivo counter for estimation of "1"8F-FGD activity incorporated into workers brains was validated. Here, we studied the calibration factor (Cf) for seven distinct voxelized computational phantoms including the reference models from ICRP 110. Computational simulations were also carried out to study the effect of increasing the distance between the detector and the brain up to 100 cm. The degree of correlation among geometric and anatomical parameters of the computational models and the calibration factors were also evaluated. The morphological diversity of the computational phantoms resulted Cf variations greater than 38% (39.8 ± 0.2 to 64.6 ± 0.5 Bq.CPS"-"1). Despite the variations, Cf has been reduced by the increasing distance, although the remarkable decrease in counting efficiency makes prohibitive this geometry. These findings suggest that head anatomic parameters can be used to improve Cf estimation. (Author)

  17. Alzheimer's Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein.

    LENUS (Irish Health Repository)

    Barry, Andrew E

    2011-05-18

    Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer\\'s disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.

  18. Intra- and extracellular pH of the brain in vivo studied by 31P-NMR during hyper- and hypocapnia

    DEFF Research Database (Denmark)

    Portman, M A; Lassen, N A; Cooper, T G

    1991-01-01

    Studies were performed to determine the pH relationships among the extracellular, intracellular, and arterial blood compartments in the brain in vivo. Resolution of the extracellular monophosphate resonance peak from the intracellular peak in 31P nuclear magnetic resonance (NMR) spectra of sheep...... brain with the calvarium intact enabled pH measurement in these respective compartments. Sheep were then subjected to both hyper- and hypoventilation, which resulted in a wide range of arterial PCO2 and pH values. Linear regression analysis of pH in these compartments yielded slopes of 0.56 +/- 0.......05 for extracellular pH (pHe) vs. arterial pH, 0.43 +/- 0.078 for intracellular pH (pHi) vs. pHe, and 0.23 +/- 0.056 for pHi vs. arterial pH. These data indicate that CO2 buffering capacity is different and decreases from the intracellular to extracellular to arterial blood compartments. Separation...

  19. Test-retest reliability of {sup 11}C-ORM-13070 in PET imaging of α{sub 2C}-adrenoceptors in vivo in the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Lehto, Jussi; Peltonen, Juha M.; Volanen, Iina; Scheinin, Mika [University of Turku, Clinical Research Services Turku CRST, Turku (Finland); TYKSLAB, Unit of Clinical Pharmacology, Turku (Finland); Virta, Jere R. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); Oikonen, Vesa; Roivainen, Anne; Luoto, Pauliina; Arponen, Eveliina; Helin, Semi; Virtanen, Kirsi [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Hietamaeki, Johanna; Holopainen, Aila; Rouru, Juha; Sallinen, Jukka [Orion Pharma, Turku (Finland); Kailajaervi, Marita [Turku Imanet, GE Healthcare, Turku (Finland); Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); University of Turku, Clinical Research Services Turku CRST, Turku (Finland)

    2015-01-15

    α{sub 2C}-Adrenoceptors share inhibitory presynaptic functions with the more abundant α{sub 2A}-adrenoceptor subtype, but they also have widespread postsynaptic modulatory functions in the brain. Research on the noradrenergic system of the human brain has been hampered by the lack of suitable PET tracers targeted to the α{sub 2}-adrenoceptor subtypes. PET imaging with the specific α{sub 2C}-adrenoceptor antagonist tracer [{sup 11}C]ORM-13070 was performed twice in six healthy male subjects to investigate the test-retest reliability of tracer binding. The bound/free ratio of tracer uptake relative to nonspecific uptake into the cerebellum during the time interval of 5 - 30 min was most prominent in the dorsal striatum: 0.77 in the putamen and 0.58 in the caudate nucleus. Absolute test-retest variability in bound/free ratios of tracer ranged from 4.3 % in the putamen to 29 % in the hippocampus. Variability was also <10 % in the caudate nucleus and thalamus. Intraclass correlation coefficients (ICC) ranged from 0.50 in the hippocampus to 0.89 in the thalamus (ICC >0.70 was also reached in the caudate nucleus, putamen, lateral frontal cortex and parietal cortex). The pattern of [{sup 11}C]ORM-13070 binding, as determined by PET, was in good agreement with receptor density results previously derived from post-mortem autoradiography. PET data analysis results obtained with a compartmental model fit, the simplified reference tissue model and a graphical reference tissue analysis method were convergent with the tissue ratio method. The results of this study support the use of [{sup 11}C]ORM-13070 PET in the quantitative assessment of α{sub 2C}-adrenoceptors in the human brain in vivo. Reliable assessment of specific tracer binding in the dorsal striatum is possible with the help of reference tissue ratios. (orig.)

  20. Experimental Evidence that In Vivo Intracerebral Administration of L-2-Hydroxyglutaric Acid to Neonatal Rats Provokes Disruption of Redox Status and Histopathological Abnormalities in the Brain.

    Science.gov (United States)

    Ribeiro, Rafael Teixeira; Zanatta, Ângela; Amaral, Alexandre Umpierrez; Leipnitz, Guilhian; de Oliveira, Francine Hehn; Seminotti, Bianca; Wajner, Moacir

    2018-04-01

    Tissue accumulation of L-2-hydroxyglutaric acid (L-2-HG) is the biochemical hallmark of L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic inherited disease characterized by neurological symptoms and brain white matter abnormalities whose pathogenesis is not yet well established. L-2-HG was intracerebrally administered to rat pups at postnatal day 1 (P1) to induce a rise of L-2-HG levels in the central nervous system (CNS). Thereafter, we investigated whether L-2-HG in vivo administration could disturb redox homeostasis and induce brain histopathological alterations in the cerebral cortex and striatum of neonatal rats. L-2-HG markedly induced the generation of reactive oxygen species (increase of 2',7'-dichloroflurescein-DCFH-oxidation), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione-GSH) and sulfhydryl content in the cerebral cortex. Alterations of the activities of various antioxidant enzymes were also observed in the cerebral cortex and striatum following L-2-HG administration. Furthermore, L-2-HG-induced lipid peroxidation and GSH decrease in the cerebral cortex were prevented by the antioxidant melatonin and by the classical antagonist of NMDA glutamate receptor MK-801, suggesting the involvement of reactive species and of overstimulation of NMDA receptor in these effects. Finally, L-2-HG provoked significant vacuolation and edema particularly in the cerebral cortex with less intense alterations in the striatum that were possibly associated with the unbalanced redox homeostasis caused by this metabolite. Taken together, it is presumed that these pathomechanisms may underlie the neurological symptoms and brain abnormalities observed in the affected patients.

  1. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study

    Directory of Open Access Journals (Sweden)

    Udvardi PT

    2013-12-01

    Full Text Available Patrick T Udvardi,1,2 Karl J Föhr,3 Carolin Henes,1,2 Stefan Liebau,2 Jens Dreyhaupt,4 Tobias M Boeckers,2 Andrea G Ludolph11Department of Child and Adolescent Psychiatry and Psychotherapy, 2Institute of Anatomy and Cell Biology, 3Department of Anaesthesiology, 4Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, GermanyAbstract: Attention-deficit/hyperactivity disorder (ADHD is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR antagonist. The compound's effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip] or saline (0.9%, ip for 21 consecutive days on postnatal days (PND 21–41. In humans, atomoxetine's earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR, mesencephalon (MES, and hippocampus (HC was analyzed either directly after treatment (PND 42 or 2 months after termination of treatment (PND 101 to assess the compound's long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine's effects

  2. Ex-vivo diffusion MRI reveals microstructural alterations in stress-sensitive brain regions: A chronic mild stress recovery study

    DEFF Research Database (Denmark)

    Khan, Ahmad Raza; Hansen, Brian; Wiborg, Ove

    Depression is a leading cause of disability worldwide and causes significant microstructural alterations in stress-sensitive brain regions. However, the potential recovery of these microstructural alterations has not previously been investigated, which we, therefore, set out to do using diffusion...... MRI (d-MRI) in the chronic mild stress (CMS) rat model of depression. This study reveals significant microstructural alterations after 8 weeks of recovery, in the opposite direction to change induced by stress in the acute phase of the experiment. Such findings may be useful in the prognosis...... of depression or for monitoring treatment response....

  3. Evaluation of brain SERT occupancy by resveratrol against MDMA-induced neurobiological and behavioral changes in rats: A 4-[¹⁸F]-ADAM/small-animal PET study.

    Science.gov (United States)

    Shih, Jui-Hu; Ma, Kuo-Hsing; Chen, Chien-Fu F; Cheng, Cheng-Yi; Pao, Li-Heng; Weng, Shao-Ju; Huang, Yuahn-Sieh; Shiue, Chyng-Yann; Yeh, Ming-Kung; Li, I-Hsun

    2016-01-01

    The misuse of 3,4-methylenedioxymethamphetamine (MDMA) has drawn a growing concern worldwide for its psychophysiological impacts on humans. MDMA abusers are often accompanied by long-term serotonergic neurotoxicity, which is associated with reduced density of cerebral serotonin transporters (SERT) and depressive disorders. Resveratrol (RSV) is a natural polyphenolic phytoalexin that has been known for its antidepressant and neuroprotective effects. However, biological targets of RSV as well as its neuroprotective effects against MDMA remained largely unknown. In this study, we examined binding potency of RSV and MDMA to SERT using small-animal positron emission tomography (PET) with the SERT radioligand, N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) and investigated the protection of RSV against the acute and long-term adverse effects of MDMA. We found that RSV exhibit binding potentials to SERT in vivo in a dose-dependent manner with variation among brain regions. When the MDMA-treated rats (10mg/kg, s.c.) were co-injected with RSV (20mg/kg, i.p.) twice daily for 4 consecutive days, MDMA-induced acute elevation in plasma corticosterone was significantly reduced. Further, 4-[(18)F]-ADAM PET imaging revealed that RSV protected against the MDMA-induced decrease in SERT availability in the midbrain and the thalamus 2 weeks following the co-treatment. The PET data were comparable to the observation from the forced swim test that RSV sufficiently ameliorated the depressive-like behaviors of the MDMA-treated rats. Together, these findings suggest that RSV is a potential antidepressant and may confer protection against neurobiological and behavioral changes induced by MDMA. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  4. In vivo measurement of regional brain metabolic response to hyperventilation using magnetic resonance: proton echo planar spectroscopic imaging (PEPSI).

    Science.gov (United States)

    Posse, S; Dager, S R; Richards, T L; Yuan, C; Ogg, R; Artru, A A; Müller-Gärtner, H W; Hayes, C

    1997-06-01

    A new rapid spectroscopic imaging technique with improved sensitivity and lipid suppression, referred to as Proton Echo Planar Spectroscopic Imaging (PEPSI), has been developed to measure the 2-dimensional distribution of brain lactate increases during hyperventilation on a conventional clinical scanner equipped with a head surface coil phased array. PEPSI images (nominal voxel size: 1.125 cm3) in five healthy subjects from an axial section approximately 20 mm inferior to the intercommissural line were obtained during an 8.5-min baseline period of normocapnia and during the final 8.5 min of a 10-min period of capnometry-controlled hyperventilation (end-tidal PCO2 of 20 mmHg). The lactate/N-acetyl aspartate signal increased significantly from baseline during hyperventilation for the insular cortex, temporal cortex, and occipital regions of both the right and left hemisphere, but not in the basal ganglia. Regional or hemispheric right-to-left differences were not found. The study extends previous work using single-voxel MR spectroscopy to dynamically study hyperventilation effects on brain metabolism.

  5. Development of methods for quantitative in vivo NMR and their application to the study of hepatic encephalopathy in the brain

    International Nuclear Information System (INIS)

    Graaf, A.A. de.

    1989-01-01

    The aim of the work presented in this thesis was to develop reliable methods for quantitative MRS that are medically relevant for the study of Hepatic Encephalopathy (HE) in rats. The required modifications of the initiation and control software of the 7 Tesla spectrometer system of the Spin Imaging group at the Technical University Delft (Netherlands), are described. Experimental methods for localized, water suppressed 1 H MRS with a surface coil, including Spectroscopic Imaging, were developed in order to solve the problems of irreproducibility and spectral overlap caused by water and lipid signals. A method for correction of line-shape distortions as a consequence of static magnetic field imperfections was developed and evaluated both theoretically and experimentally. An approach to solve the problems in the quantification of the 1 H MRS spectra, caused especially by spectral overlap, frequency dependent intensity distortions and intensity modulations in coupled spin systems, was developed and evaluated. The brain energy state during HE was investigated using 31 P MRS. The developed methods for quantitative 1 H MRS were applied to monitor the concentrations of severeal important brain amino acids and other metabolic compounds during the development of acute HE, and during the development of ammonia induced encephalopathy in two different animal models. (author). 201 refs.; 32 figs.; 28 schemes.; 11 tabs

  6. Blockade of cannabinoid CB receptor function protects against in vivo disseminating brain damage following NMDA-induced excitotoxicity

    DEFF Research Database (Denmark)

    Hansen, H.H.; Ramos, J.A.; Fernández-Ruiz, J.

    2002-01-01

    -induced excitotoxic damage in the ipsilateral forebrain was not influenced by agonist-stimulated CB receptor function. In contrast, blockade of CB, but not CB, receptor activity evoked a robust neuroprotective response by reducing the infarct area and the number of cortical degenerating neurons. These results suggest...... receptor function on NMDA-induced excitotoxicity. Neonatal (6-day-old) rat pups received a systemic injection of a mixed CB/CB receptor agonist (WIN55,212-2) or their respective antagonists (SR141716A for CB and SR144528 for CB) prior to an unilateral intrastriatal microinjection of NMDA. The NMDA...... a critical involvement of CB receptor tonus on neuronal survival following NMDA receptor-induced excitotoxicity in vivo....

  7. High Antifouling Property of Ion-Selective Membrane: toward In Vivo Monitoring of pH Change in Live Brain of Rats with Membrane-Coated Carbon Fiber Electrodes.

    Science.gov (United States)

    Hao, Jie; Xiao, Tongfang; Wu, Fei; Yu, Ping; Mao, Lanqun

    2016-11-15

    In vivo monitoring of pH in live brain remains very essential to understanding acid-base chemistry in various physiological processes. This study demonstrates a potentiometric method for in vivo monitoring of pH in the central nervous system with carbon fiber-based proton-selective electrodes (CF-H + ISEs) with high antifouling property. The CF-H + ISEs are prepared by formation of a H + -selective membrane (H + ISM) with polyvinyl chloride polymeric matrixes containing plasticizer bis(2-ethylhexyl)sebacate, H + ionophore tridodecylamine, and ion exchanger potassium tetrakis(4-chlorophenyl)borate onto carbon fiber electrodes (CFEs). Both in vitro and in vivo studies demonstrate that the H + ISM exhibits strong antifouling property against proteins, which enables the CF-H + ISEs to well maintain the sensitivity and reversibility for pH sensing after in vivo measurements. Moreover, the CF-H + ISEs exhibit a good response to pH changes within a narrow physiological pH range from 6.0 to 8.0 in quick response time with high reversibility and selectivity against species endogenously existing in the central nervous system. The applicability of the CF-H + ISEs is illustrated by real-time monitoring of pH changes during acid-base disturbances, in which the brain acidosis is induced by CO 2 inhalation and brain alkalosis is induced by bicarbonate injections. The results demonstrate that brain pH value rapidly decreases in the amygdaloid nucleus by ca. 0.14 ± 0.01 (n = 5) when the rats breath in pure CO 2 gas, while increases in the cortex by about 0.77 ± 0.12 (n = 3) following intraperitoneal injection of 5 mmol/kg NaHCO 3 . This study demonstrates a new potentiometric method for in vivo measurement of pH change in the live brain of rats with high reliability.

  8. In vivo high angular resolution diffusion-weighted imaging of mouse brain at 16.4 Tesla.

    Directory of Open Access Journals (Sweden)

    Othman I Alomair

    Full Text Available Magnetic Resonance Imaging (MRI of the rodent brain at ultra-high magnetic fields (> 9.4 Tesla offers a higher signal-to-noise ratio that can be exploited to reduce image acquisition time or provide higher spatial resolution. However, significant challenges are presented due to a combination of longer T1 and shorter T2/T2* relaxation times and increased sensitivity to magnetic susceptibility resulting in severe local-field inhomogeneity artefacts from air pockets and bone/brain interfaces. The Stejskal-Tanner spin echo diffusion-weighted imaging (DWI sequence is often used in high-field rodent brain MRI due to its immunity to these artefacts. To accurately determine diffusion-tensor or fibre-orientation distribution, high angular resolution diffusion imaging (HARDI with strong diffusion weighting (b >3000 s/mm2 and at least 30 diffusion-encoding directions are required. However, this results in long image acquisition times unsuitable for live animal imaging. In this study, we describe the optimization of HARDI acquisition parameters at 16.4T using a Stejskal-Tanner sequence with echo-planar imaging (EPI readout. EPI segmentation and partial Fourier encoding acceleration were applied to reduce the echo time (TE, thereby minimizing signal decay and distortion artefacts while maintaining a reasonably short acquisition time. The final HARDI acquisition protocol was achieved with the following parameters: 4 shot EPI, b = 3000 s/mm2, 64 diffusion-encoding directions, 125×150 μm2 in-plane resolution, 0.6 mm slice thickness, and 2h acquisition time. This protocol was used to image a cohort of adult C57BL/6 male mice, whereby the quality of the acquired data was assessed and diffusion tensor imaging (DTI derived parameters were measured. High-quality images with high spatial and angular resolution, low distortion and low variability in DTI-derived parameters were obtained, indicating that EPI-DWI is feasible at 16.4T to study animal models of white

  9. Three-dimensional histological imaging of primate brain and correlation with in vivo medical device images Imagerie histologique tri-dimensionnelle du cerveau de primate et corrélation avec l'imagerie médicale in vivo

    Directory of Open Access Journals (Sweden)

    Julien Dauguet

    2011-02-01

    Full Text Available The 3D reconstruction of series of histological slices is an imaging technique that appeared about 25 years ago but that is only starting now to become recognized as an imaging modality per se. Thanks to this technique, it becomes possible to restore the spatial consistency of the brain and to match accurately histological slices with an in vivo medical device image such as an MRI or a PET scan. This is of high interest since it allows direct comparison between the histology, often considered as the gold standard in terms of information, and the same medical devices used in clinical routine to image human patients. Thanks to the similarity of their brain with humans and the disease models widely developed for them, non-human primates are privileged species to benefit from this possibility of 3D analysis and in vivo - post mortem correlation. We present in this article a state of the art review of the main techniques proposed to achieve this original imaging technique, followed by a set of some particularly promising neuroimaging applications.La reconstruction 3D de séries de coupes histologiques est une technique d'imagerie qui est apparue il y a 25 ans environ mais qui commence seulement à être reconnue comme une modalité d'imagerie à part entière. Grâce à cette technique, la cohérence 3D du cerveau est rétablie et il devient notamment possible de mettre en correspondance précisément des coupes histologiques avec un examen issu d'un imageur médical comme une IRM ou une TEP. C'est d'un intérêt majeur car cela permet une comparaison directe entre l'histologie, souvent considérée comme la référence étalon en termes d'information fournie, et les mêmes imageurs médicaux que ceux utilisés en routine clinique pour suivre les patients humains. Grâce à leur similarité avec les humains et aux nombreux modèles animaux de maladies développés pour eux, les primates non-humains sont une espèce privilégiée pour bénéficier de

  10. Detection of the in vivo conversion of 2-pyrrolidinone to gamma-aminobutyric acid in mouse brain.

    Science.gov (United States)

    Callery, P S; Stogniew, M; Geelhaar, L A

    1979-01-01

    Labeled gamma-aminobutyric acid was detected in mouse brain following intravenous injections of deuterium labeled 2-pyrrolidinone. [2H6]Pyrrolidinone was prepared by the reduction of [2H4]succinimide with lithium aluminum deuteride. Quantification was accomplished by a gas chromatography mass spectrometry assay method. gamma-Aminobutyric acid and internal standard, 5-aminovaleric acid, were converted to volatile derivatives by treatment with N,N-dimethylformamide dimethyl acetal. Quantitative estimates were derived from peak area measurements obtained from monitoring the parent ions of the gamma-aminobutyric acid and internal standard derivatives by repetitive scanning during the GC run. The conversion of pyrrolidinone to gamma-aminobutyric acid may provide a method for labeling central gamma-aminobutyric acid pools.

  11. Brain GABA Detection in vivo with the J-editing 1H MRS Technique: A Comprehensive Methodological Evaluation of Sensitivity Enhancement, Macromolecule Contamination and Test-Retest Reliability

    Science.gov (United States)

    Shungu, Dikoma C.; Mao, Xiangling; Gonzales, Robyn; Soones, Tacara N.; Dyke, Jonathan P.; van der Veen, Jan Willem; Kegeles, Lawrence S.

    2016-01-01

    Abnormalities in brain γ-aminobutyric acid (GABA) have been implicated in various neuropsychiatric and neurological disorders. However, in vivo GABA detection by proton magnetic resonance spectroscopy (1H MRS) presents significant challenges arising from low brain concentration, overlap by much stronger resonances, and contamination by mobile macromolecule (MM) signals. This study addresses these impediments to reliable brain GABA detection with the J-editing difference technique on a 3T MR system in healthy human subjects by (a) assessing the sensitivity gains attainable with an 8-channel phased-array head coil, (b) determining the magnitude and anatomic variation of the contamination of GABA by MM, and (c) estimating the test-retest reliability of measuring GABA with this method. Sensitivity gains and test-retest reliability were examined in the dorsolateral prefrontal cortex (DLPFC), while MM levels were compared across three cortical regions: the DLPFC, the medial prefrontal cortex (MPFC) and the occipital cortex (OCC). A 3-fold higher GABA detection sensitivity was attained with the 8-channel head coil compared to the standard single-channel head coil in DLPFC. Despite significant anatomic variation in GABA+MM and MM across the three brain regions (p GABA+MM was relatively stable across the three voxels, ranging from 41% to 49%, a non-significant regional variation (p = 0.58). The test-retest reliability of GABA measurement, expressed either as ratios to voxel tissue water (W) or total creatine, was found to be very high for both the single-channel coil and the 8-channel phased-array coil. For the 8-channel coil, for example, Pearson’s correlation coefficient of test vs. retest for GABA/W was 0.98 (R2 = 0.96, p = 0.0007), the percent coefficient of variation (CV) was 1.25%, and the intraclass correlation coefficient (ICC) was 0.98. Similar reliability was also found for the co-edited resonance of combined glutamate and glutamine (Glx) for both coils. PMID

  12. Early detection of ventilation-induced brain injury using magnetic resonance spectroscopy and diffusion tensor imaging: an in vivo study in preterm lambs.

    Directory of Open Access Journals (Sweden)

    Béatrice Skiöld

    Full Text Available BACKGROUND AND AIM: High tidal volume (VT ventilation during resuscitation of preterm lambs results in brain injury evident histologically within hours after birth. We aimed to investigate whether magnetic resonance spectroscopy (MRS and/or diffusion tensor imaging (DTI can be used for early in vivo detection of ventilation-induced brain injury in preterm lambs. METHODS: Newborn lambs (0.85 gestation were stabilized with a "protective ventilation" strategy (PROT, n = 7: prophylactic Curosurf, sustained inflation, VT 7 mL/kg, positive end expiratory pressure (PEEP 5 cmH2O or an initial 15 minutes of "injurious ventilation" (INJ, n = 10: VT 12 mL/kg, no PEEP, late Curosurf followed by PROT ventilation for the remainder of the experiment. At 1 hour, lambs underwent structural magnetic resonance imaging (Siemens, 3 Tesla. For measures of mean/axial/radial diffusivity (MD, AD, RD and fractional anisotropy (FA, 30 direction DTI was performed. Regions of interests encompassed the thalamus, internal capsule, periventricular white matter and the cerebellar vermis. MRS was performed using a localized single-voxel (15×15×20 mm3, echo time 270 ms encompassing suptratentorial deep nuclear grey matter and central white matter. Peak-area ratios for lactate (Lac relative to N-acetylaspartate (NAA, choline (Cho and creatine (Cr were calculated. Groups were compared using 2-way RM-ANOVA, Mann-Whitney U-test and Spearman's correlations. RESULTS: No cerebral injury was seen on structural MR images. Lambs in the INJ group had higher mean FA and lower mean RD in the thalamus compared to PROT lambs, but not in the other regions of interest. Peak-area lactate ratios >1.0 was only seen in INJ lambs. A trend of higher mean peak-area ratios for Lac/Cr and Lac/Cho was seen, which correlated with lower pH in both groups. CONCLUSION: Acute changes in brain diffusion measures and metabolite peak-area ratios were observed after injurious ventilation. Early MRS/DTI is

  13. In vivo estimation of transverse relaxation time constant (T2 ) of 17 human brain metabolites at 3T.

    Science.gov (United States)

    Wyss, Patrik O; Bianchini, Claudio; Scheidegger, Milan; Giapitzakis, Ioannis A; Hock, Andreas; Fuchs, Alexander; Henning, Anke

    2018-08-01

    The transverse relaxation times T 2 of 17 metabolites in vivo at 3T is reported and region specific differences are addressed. An echo-time series protocol was applied to one, two, or three volumes of interest with different fraction of white and gray matter including a total number of 106 healthy volunteers and acquiring a total number of 128 spectra. The data were fitted with the 2D fitting tool ProFit2, which included individual line shape modeling for all metabolites and allowed the T 2 calculation of 28 moieties of 17 metabolites. The T 2 of 10 metabolites and their moieties have been reported for the first time. Region specific T 2 differences in white and gray matter enriched tissue occur in 16 of 17 metabolites examined including single resonance lines and coupled spin systems. The relaxation time T 2 is regions specific and has to be considered when applying tissue composition correction for internal water referencing. Magn Reson Med 80:452-461, 2018. © 2018 International Society for Magnetic Resonance in Medicine. © 2018 International Society for Magnetic Resonance in Medicine.

  14. T cells' immunological synapses induce polarization of brain astrocytes in vivo and in vitro: a novel astrocyte response mechanism to cellular injury.

    Science.gov (United States)

    Barcia, Carlos; Sanderson, Nicholas S R; Barrett, Robert J; Wawrowsky, Kolja; Kroeger, Kurt M; Puntel, Mariana; Liu, Chunyan; Castro, Maria G; Lowenstein, Pedro R

    2008-08-20

    Astrocytes usually respond to trauma, stroke, or neurodegeneration by undergoing cellular hypertrophy, yet, their response to a specific immune attack by T cells is poorly understood. Effector T cells establish specific contacts with target cells, known as immunological synapses, during clearance of virally infected cells from the brain. Immunological synapses mediate intercellular communication between T cells and target cells, both in vitro and in vivo. How target virally infected astrocytes respond to the formation of immunological synapses established by effector T cells is unknown. Herein we demonstrate that, as a consequence of T cell attack, infected astrocytes undergo dramatic morphological changes. From normally multipolar cells, they become unipolar, extending a major protrusion towards the immunological synapse formed by the effector T cells, and withdrawing most of their finer processes. Thus, target astrocytes become polarized towards the contacting T cells. The MTOC, the organizer of cell polarity, is localized to the base of the protrusion, and Golgi stacks are distributed throughout the protrusion, reaching distally towards the immunological synapse. Thus, rather than causing astrocyte hypertrophy, antiviral T cells cause a major structural reorganization of target virally infected astrocytes. Astrocyte polarization, as opposed to hypertrophy, in response to T cell attack may be due to T cells providing a very focused attack, and thus, astrocytes responding in a polarized manner. A similar polarization of Golgi stacks towards contacting T cells was also detected using an in vitro allogeneic model. Thus, different T cells are able to induce polarization of target astrocytes. Polarization of target astrocytes in response to immunological synapses may play an important role in regulating the outcome of the response of astrocytes to attacking effector T cells, whether during antiviral (e.g. infected during HIV, HTLV-1, HSV-1 or LCMV infection), anti

  15. T cells' immunological synapses induce polarization of brain astrocytes in vivo and in vitro: a novel astrocyte response mechanism to cellular injury.

    Directory of Open Access Journals (Sweden)

    Carlos Barcia

    2008-08-01

    Full Text Available Astrocytes usually respond to trauma, stroke, or neurodegeneration by undergoing cellular hypertrophy, yet, their response to a specific immune attack by T cells is poorly understood. Effector T cells establish specific contacts with target cells, known as immunological synapses, during clearance of virally infected cells from the brain. Immunological synapses mediate intercellular communication between T cells and target cells, both in vitro and in vivo. How target virally infected astrocytes respond to the formation of immunological synapses established by effector T cells is unknown.Herein we demonstrate that, as a consequence of T cell attack, infected astrocytes undergo dramatic morphological changes. From normally multipolar cells, they become unipolar, extending a major protrusion towards the immunological synapse formed by the effector T cells, and withdrawing most of their finer processes. Thus, target astrocytes become polarized towards the contacting T cells. The MTOC, the organizer of cell polarity, is localized to the base of the protrusion, and Golgi stacks are distributed throughout the protrusion, reaching distally towards the immunological synapse. Thus, rather than causing astrocyte hypertrophy, antiviral T cells cause a major structural reorganization of target virally infected astrocytes.Astrocyte polarization, as opposed to hypertrophy, in response to T cell attack may be due to T cells providing a very focused attack, and thus, astrocytes responding in a polarized manner. A similar polarization of Golgi stacks towards contacting T cells was also detected using an in vitro allogeneic model. Thus, different T cells are able to induce polarization of target astrocytes. Polarization of target astrocytes in response to immunological synapses may play an important role in regulating the outcome of the response of astrocytes to attacking effector T cells, whether during antiviral (e.g. infected during HIV, HTLV-1, HSV-1 or LCMV

  16. Occupational rhinitis.

    Science.gov (United States)

    Petrick, Maria M; Slavin, Raymond G

    2003-05-01

    This article aims to define occupational rhinitis, classify its various causes, review the steps in its diagnosis, and describe its nonpharmacologic and pharmacologic principles of management. Occupational rhinitis frequently coexists with asthma but also occurs alone. Although it does not have the same impact as occupational asthma, occupational rhinitis causes distress, discomfort, and work inefficiency. By concentrating on the patient's workplace, the clinician has an opportunity to practice preventive medicine: to recognize substances in the patient's micro- and macroenvironment that are causing the problems and then to intervene by altering the environment or removing the patient from the environment.

  17. Neonatal domoic acid decreases in vivo binding of [11C]yohimbine to α2 adrenoceptors in adult rat brain

    DEFF Research Database (Denmark)

    Thomsen, Majken; Lillethorup, Thea Pinholt; Jakobsen, Steen

    -quantitative analysis. MicroPET images were analyzed using PMOD software and registered to an average Sprague-Dawley rat MRI brain atlas to acquire data in limbic and cortical regions of interest. Results: In behavioural testing DOM60, and to a lesser extent DOM20 rats, spent more time in the periphery during the open......-Dawley rats (n=6-7 per group) were injected (s.c.) daily from postnatal day 8-14 with saline or one of two low sub-convulsive doses, 20µg/kg [DOM20] or 60µg/kg [DOM60] of DOM, an AMPA/kainate receptor agonist. The behaviour of the rats was observed in an open field test, a social interaction test...... and the forced swim test at day 50, 75 and 98, respectively. At ~120 days of age 3-4 rats per group were injected with [11C]yohimbine, an α2 adrenergic receptor antagonist, and scanned in a Mediso micro positron emission tomography (PET) scanner, to measure α2 adrenoceptor binding. The volume of distribution (VT...

  18. Widespread promoter methylation of synaptic plasticity genes in long-term potentiation in the adult brain in vivo.

    Science.gov (United States)

    Maag, Jesper L V; Kaczorowski, Dominik C; Panja, Debabrata; Peters, Timothy J; Bramham, Clive R; Wibrand, Karin; Dinger, Marcel E

    2017-03-23

    DNA methylation is a key modulator of gene expression in mammalian development and cellular differentiation, including neurons. To date, the role of DNA modifications in long-term potentiation (LTP) has not been explored. To investigate the occurrence of DNA methylation changes in LTP, we undertook the first detailed study to describe the methylation status of all known LTP-associated genes during LTP induction in the dentate gyrus of live rats. Using a methylated DNA immunoprecipitation (MeDIP)-array, together with previously published matched RNA-seq and public histone modification data, we discover widespread changes in methylation status of LTP-genes. We further show that the expression of many LTP-genes is correlated with their methylation status. We show that these correlated genes are enriched for RNA-processing, active histone marks, and specific transcription factors. These data reveal that the synaptic activity-evoked methylation changes correlates with pre-existing activation of the chromatin landscape. Finally, we show that methylation of Brain-derived neurotrophic factor (Bdnf) CpG-islands correlates with isoform switching from transcripts containing exon IV to exon I. Together, these data provide the first evidence of widespread regulation of methylation status in LTP-associated genes.

  19. In vivo quantitative imaging of dopamine receptors in human brain using positron emission tomography and (XWBr)bromospiperone

    Energy Technology Data Exchange (ETDEWEB)

    Maziere, B; Loc' h, C; Barton, J -C; Sgouropoulos, P; Duquesnoy, N; Antona, R d' ; Cambon, H

    1985-08-27

    The brain regional distribution and kinetics of (XWBr)bromospiperone, a derivative of a neuroleptic (spiperone) labeled with the positron emitter bromine-76, were studied by time-of-flight tomography after i.v. injection in man. In a control subject the kinetic distribution study showed an accumulation of radioactivity which reached a maximum 3 h postinjection in the frontal cortex and cerebellum regions and 4-5 h postinjection in the basal ganglia. Thereafter the striatal activity remained essentially constant over a period of 25 h. In a group of 13 control subjects, the mean value for the striatum-to-cerebellum ratio, at 4.5 h postinjection, was 1.84 (S.D. 0.21). In two schizophrenics treated with high doses of haloperidol, this ratio was found to be only 1.22. These data indicate that radiolabeled bromospiperone is very suitable for human pharmacological or pathological investigations of the central dopaminergic system. (Auth.). 20 refs.; 3 figs.; 1 table.

  20. Neonatal domoic acid decreases in vivo binding of [11C]yohimbine to α2 adrenoceptors in adult rat brain

    DEFF Research Database (Denmark)

    Thomsen, Majken; Lillethorup, Thea Pinholt; Jakobsen, Steen

    day 8-14 with saline or one of two low sub-convulsive doses, 20µg/kg [DOM20] or 60µg/kg [DOM60] of DOM, an AMPA/kainate receptor agonist. The behaviour of the rats was observed in an open field test, a social interaction test and the forced swim test at day 50, 75 and 98, respectively. At ~120 days...... of age 3-4 rats per group were injected with [11C]yohimbine, an α2 adrenergic receptor antagonist and scanned in a micro positron emission tomography (PET) scanner. DOM60 spent more time in the periphery during the open field test and less time struggling in the forced swim test compared to the saline...... treated rats. microPET data revealed that DOM60 rats had a 40-47 % reduction in [11C]yohimbine binding in limbic and cortical brain regions relative to saline treated rats. We conclude that neonatal administration of DOM combined with the potential stress associated with behavioural testing results...

  1. Concomitants of alcoholism: differential effects of thiamine deficiency, liver damage, and food deprivation on the rat brain in vivo.

    Science.gov (United States)

    Zahr, Natalie M; Sullivan, Edith V; Rohlfing, Torsten; Mayer, Dirk; Collins, Amy M; Luong, Richard; Pfefferbaum, Adolf

    2016-07-01

    Serious neurological concomitants of alcoholism include Wernicke's encephalopathy (WE), Korsakoff's syndrome (KS), and hepatic encephalopathy (HE). This study was conducted in animal models to determine neuroradiological signatures associated with liver damage caused by carbon tetrachloride (CCl4), thiamine deficiency caused by pyrithiamine treatment, and nonspecific nutritional deficiency caused by food deprivation. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were used to evaluate brains of wild-type Wistar rats at baseline and following treatment. Similar to observations in ethanol (EtOH) exposure models, thiamine deficiency caused enlargement of the lateral ventricles. Liver damage was not associated with effects on cerebrospinal fluid volumes, whereas food deprivation caused modest enlargement of the cisterns. In contrast to what has repeatedly been shown in EtOH exposure models, in which levels of choline-containing compounds (Cho) measured by MRS are elevated, Cho levels in treated animals in all three experiments (i.e., liver damage, thiamine deficiency, and food deprivation) were lower than those in baseline or controls. These results add to the growing body of literature suggesting that MRS-detectable Cho is labile and can depend on a number of variables that are not often considered in human experiments. These results also suggest that reductions in Cho observed in humans with alcohol use disorder (AUD) may well be due to mild manifestations of concomitants of AUD such as liver damage or nutritional deficiencies and not necessarily to alcohol consumption per se.

  2. In vivo vitamin C deficiency in guinea pigs increases ascorbate transporters in liver but not kidney and brain.

    Science.gov (United States)

    Søgaard, Ditte; Lindblad, Maiken M; Paidi, Maya D; Hasselholt, Stine; Lykkesfeldt, Jens; Tveden-Nyborg, Pernille

    2014-07-01

    Moderate vitamin C (vitC) deficiency (plasma concentrations less than 23 μmol/L) affects as much as 10% of adults in the Western World and has been associated with an increased mortality in disease complexes such as cardiovascular disease and the metabolic syndrome. The distribution of vitC within the body is subjected to complex and nonlinear pharmacokinetics and largely depends on the sodium-dependent vitC-specific transporters, sodium-dependent vitamin C transporter 1 (SVCT1) and sodium-dependent vitamin C transporter 2 (SVCT2). Although currently not established, it is likely to expect that a state of deficiency may affect the expression of these transporters to preserve vitC concentrations in specific target tissues. We hypothesized that diet-induced states of vitC deficiency lead to alterations in the messenger RNA (mRNA) and/or protein expression of vitC transporters, thereby regulating vitC tissue distribution. Using guinea pigs as a validated model, this study investigated the effects of a diet-induced vitC deficiency (100 mg vitC/kg feed) or depletion (0 mg vitC/kg feed) on the expression of transporters SVCT1 and SVCT2 in selected tissues and the transport from plasma to cerebrospinal fluid (CSF). In deficient animals, SVCT1 was increased in the liver, whereas a decreased SVCT1 expression but increased SVCT2 mRNA in livers of depleted animals suggests a shift in transporter expression as response to the diet. In CSF, a constant plasma:CSF ratio shows unaltered vitC transport irrespective of dietary regime. The study adds novel information to the complex regulation maintaining vitC homeostasis in vivo during states of deficiency. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Long-term Neuroglial Cocultures as a Brain Aging Model: Hallmarks of Senescence, MicroRNA Expression Profiles, and Comparison With In Vivo Models.

    Science.gov (United States)

    Bigagli, Elisabetta; Luceri, Cristina; Scartabelli, Tania; Dolara, Piero; Casamenti, Fiorella; Pellegrini-Giampietro, Domenico E; Giovannelli, Lisa

    2016-01-01

    Our purpose was to evaluate long-term neuroglial cocultures as a model for investigating senescence in the nervous system and to assess its similarities with in vivo models. To this aim, we maintained the cultures from 15 days in vitro (mature cultures) up to 27 days in vitro (senescent cultures), measuring senescence-associated, neuronal, dendritic, and astrocytic markers. Whole microRNA expression profiles were compared with those measured in the cortex of 18- and 24-month-old C57Bl/6J aged mice and of transgenic TgCRND8 mice, a model of amyloid-β deposition. Neuroglial cocultures displayed features of cellular senescence (increased senescence-associated-β-galactosidase activity, oxidative stress, γ-H2AX expression, IL-6 production, astrogliosis) that were concentration dependently counteracted by the antiaging compound resveratrol (1-5 µM). Among the 1,080 microRNAs analyzed, 335 were downregulated or absent in 27 compared with 15 days in vitro and resveratrol reversed this effect. A substantial overlapping was found between age-associated changes in microRNA expression profiles in vitro and in TgCRND8 mice but not in physiologically aged mice, indicating that this culture model displays more similarities with pathological than physiological brain aging. Our results demonstrate that neuroglial cocultures aged in vitro can be useful for investigating the cellular and molecular mechanisms of brain aging and for preliminary testing of protective compounds. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Development of an imaging system for in vivo real-time monitoring of neuronal activity in deep brain of free-moving rats.

    Science.gov (United States)

    Iijima, Norio; Miyamoto, Shinji; Matsumoto, Keisuke; Takumi, Ken; Ueta, Yoichi; Ozawa, Hitoshi

    2017-09-01

    We have newly developed a system that allows monitoring of the intensity of fluorescent signals from deep brains of rats transgenically modified to express enhanced green fluorescent protein (eGFP) via an optical fiber. One terminal of the optical fiber was connected to a blue semiconductor laser oscillator/green fluorescence detector. The other terminal was inserted into the vicinity of the eGFP-expressing neurons. Since the optical fiber was vulnerable to twisting stresses caused by animal movement, we also developed a cage in which the floor automatically turns, in response to the turning of the rat's head. This relieved the twisting stress on the optical fiber. The system then enabled real-time monitoring of fluorescence in awake and unrestrained rats over many hours. Using this system, we could continuously monitor eGFP-expression in arginine vasopressin-eGFP transgenic rats. Moreover, we observed an increase of eGFP-expression in the paraventricular nucleus under salt-loading conditions. We then performed in vivo imaging of eGFP-expressing GnRH neurons in the hypothalamus, via a bundle consisting of 3000 thin optical fibers. With the combination of the optical fiber bundle connection to the fluorescence microscope, and the special cage system, we were able to capture and retain images of eGFP-expressing neurons from free-moving rats. We believe that our newly developed method for monitoring and imaging eGFP-expression in deep brain neurons will be useful for analysis of neuronal functions in awake and unrestrained animals for long durations.

  5. Effects of γ-Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and γ-Aminobutyric acid metabolism in the anesthetized rat In vivo.

    Science.gov (United States)

    Patel, Anant B; de Graaf, Robin A; Rothman, Douglas L; Behar, Kevin L

    2015-07-01

    γ-Aminobutyric acid (GABA) clearance from the extracellular space after release from neurons involves reuptake into terminals and astrocytes through GABA transporters (GATs). The relative flows through these two pathways for GABA released from neurons remains unclear. This study determines the effect of tiagabine, a selective inhibitor of neuronal GAT-1, on the rates of glutamate (Glu) and GABA metabolism and GABA resynthesis via the GABA-glutamine (Gln) cycle. Halothane-anesthetized rats were administered tiagabine (30 mg/kg, i.p.) and 45 min later received an intravenous infusion of either [1,6-(13)C2]glucose (in vivo) or [2-(13)C]acetate (ex vivo). Nontreated rats served as controls. Metabolites and (13)C enrichments were measured with (1)H-[(13)C]-nuclear magnetic resonance spectroscopy and referenced to their corresponding endpoint values measured in extracts from in situ frozen brain. Metabolic flux estimates of GABAergic and glutamatergic neurons were determined by fitting a metabolic model to the (13)C turnover data measured in vivo during [1,6-(13)C2]glucose infusion. Tiagabine-treated rats were indistinguishable (P > 0.05) from controls in tissue amino acid levels and in (13)C enrichments from [2-(13)C]acetate. Tiagabine reduced average rates of glucose oxidation and neurotransmitter cycling in both glutamatergic neurons (↓18%, CMR(glc(ox)Glu): control, 0.27 ± 0.05 vs. tiagabine, 0.22 ± 0.04 µmol/g/min; ↓11%, V(cyc(Glu-Gln)): control 0.23 ± 0.05 vs. tiagabine 0.21 ± 0.04 µmol/g/min and GABAergic neurons (↓18-25%, CMR(glc(ox)GABA): control 0.09 ± 0.02 vs. tiagabine 0.07 ± 0.03 µmol/g/min; V(cyc(GABA-Gln)): control 0.08 ± 0.02 vs. tiagabine 0.07 ± 0.03 µmol/g/min), but the changes in glutamatergic and GABAergic fluxes were not significant (P > 0.10). The results suggest that any reduction in GABA metabolism by tiagabine might be an indirect response to reduced glutamatergic drive rather than direct compensatory effects. © 2015 Wiley

  6. Swept-source optical coherence tomography powered by a 1.3-μm vertical cavity surface emitting laser enables 2.3-mm-deep brain imaging in mice in vivo

    Science.gov (United States)

    Choi, Woo June; Wang, Ruikang K.

    2015-10-01

    We report noninvasive, in vivo optical imaging deep within a mouse brain by swept-source optical coherence tomography (SS-OCT), enabled by a 1.3-μm vertical cavity surface emitting laser (VCSEL). VCSEL SS-OCT offers a constant signal sensitivity of 105 dB throughout an entire depth of 4.25 mm in air, ensuring an extended usable imaging depth range of more than 2 mm in turbid biological tissue. Using this approach, we show deep brain imaging in mice with an open-skull cranial window preparation, revealing intact mouse brain anatomy from the superficial cerebral cortex to the deep hippocampus. VCSEL SS-OCT would be applicable to small animal studies for the investigation of deep tissue compartments in living brains where diseases such as dementia and tumor can take their toll.

  7. Mapping of electrophysiological response to transcranial infrared laser stimulation on the human brain in vivo measured by electroencephalography (Conference Presentation)

    Science.gov (United States)

    Wang, Xinlong; Reddy, Divya Dhandapani; Gonzalez-Lima, F.; Liu, Hanli

    2017-02-01

    Transcranial infrared laser stimulation (TILS) is a non-destructive and non-thermal photobiomodulation therapy or process on the human brain; TILS uses infrared light from lasers or LEDs and has gained increased recognition for its beneficial effects on a variety of neurological and psychological conditions. While the mechanism of TILS has been assumed to stem from cytochrome-c-oxidase (CCO), which is the last enzyme in the electron transportation chain and is the primary photoacceptor, no literature is found to report electrophysiological response to TILS. In this study, a 64-channel electroencephalography (EEG) system was employed to monitor electrophysiological activities from 15 healthy human participants before, during and after TILS. A placebo experimental protocol was also applied for rigorous comparison. After recording a 3-minute baseline, we applied a 1064-nm laser with a power of 3.5W on the right forehead of each human participant for 8 minutes, followed by a 5-minute recovery period. In 64-channel EEG data analysis, we utilized several methods (root mean square, principal component analysis followed by independent component analysis, permutation conditional mutual information, and time-frequency wavelet analysis) to reveal differences in electrophysiological response to TILS between the stimulated versus placebo group. The analyzed results were further investigated using general linear model and paired t-test to reveal statistically meaningful responses induced by TILS. Moreover, this study will provide spatial mapping of human electrophysiological and possibly neural network responses to TILS for first time, indicating the potential of EEG to be an effective method for monitoring neurological improvement induced by TILS.

  8. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study

    Science.gov (United States)

    Udvardi, Patrick T; Föhr, Karl J; Henes, Carolin; Liebau, Stefan; Dreyhaupt, Jens; Boeckers, Tobias M; Ludolph, Andrea G

    2013-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound’s effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B) are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip]) or saline (0.9%, ip) for 21 consecutive days on postnatal days (PND) 21–41. In humans, atomoxetine’s earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR), mesencephalon (MES), and hippocampus (HC) was analyzed either directly after treatment (PND 42) or 2 months after termination of treatment (PND 101) to assess the compound’s long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine’s effects beyond NET inhibition. Taken together, these data reveal that atomoxetine seems to decrease glutamatergic transmission in a brain region-specific manner. Long-term data show that the compound’s impact is not due to an acute pharmacological effect but lasts or even amplifies after a drug-free period of 2 months, leading to altered development of

  9. Effects of Long-Term Caffeine Consumption on the Adenosine A1 Receptor in the Rat Brain: an In Vivo PET Study with [18F]CPFPX.

    Science.gov (United States)

    Nabbi-Schroeter, Danje; Elmenhorst, David; Oskamp, Angela; Laskowski, Stefanie; Bauer, Andreas; Kroll, Tina

    2018-04-01

    Caffeine, a nonselective antagonist of adenosine receptors, is the most popular psychostimulant worldwide. Recently, a protective role of moderate chronic caffeine consumption against neurodegenerative diseases such as Alzheimer's and Parkinson's disease has been discussed. Thus, aim of the present study was an in vivo investigation of effects of long-term caffeine consumption on the adenosine A 1 receptor (A 1 AR) in the rat brain. Sixteen adult, male rats underwent five positron emission tomography (PET) scans with the highly selective A 1 AR radioligand [ 18 F]CPFPX in order to determine A 1 AR availability. After the first baseline PET scan, the animals were assigned to two groups: Caffeine treatment and control group. The caffeine-treated animals received caffeinated tap water (30 mg/kg bodyweight/day, corresponding to 4-5 cups of coffee per day in humans) for 12 weeks. Subsequently, caffeine was withdrawn and repeated PET measurements were performed on day 1, 2, 4, and 7 of caffeine withdrawal. The control animals were measured according to the same time schedule. At day 1, after 4.4 h of caffeine withdrawal, a significant decrease (- 34.5%, p < 0.001) of whole brain A 1 AR availability was observed. Unlike all other investigated brain regions in caffeine-treated rats, the hypothalamus and nucleus accumbens showed no significant intraindividual differences between baseline and first withdrawal PET scan. After approximately 27 h of caffeine withdrawal, the region- and group-specific effects disappeared and A 1 AR availability settled around baseline. The present study provides evidence that chronic caffeine consumption does not lead to persistent changes in functional availability of cerebral A 1 ARs which have previously been associated with neuroprotective effects of caffeine. The acute and region-specific decrease in cerebral A 1 AR availability directly after caffeine withdrawal is most likely caused by residual amounts of caffeine metabolites

  10. Central Administration of Lipopolysaccharide Induces Depressive-like Behavior in Vivo and Activates Brain Indoleamine 2,3 Dioxygenase In Murine Organotypic Hippocampal Slice Cultures

    Directory of Open Access Journals (Sweden)

    Kavelaars Annemieke

    2010-08-01

    Full Text Available Abstract Background Transient stimulation of the innate immune system by an intraperitoneal injection of lipopolysaccharide (LPS activates peripheral and central expression of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO which mediates depressive-like behavior. It is unknown whether direct activation of the brain with LPS is sufficient to activate IDO and induce depressive-like behavior. Methods Sickness and depressive-like behavior in C57BL/6J mice were assessed by social exploration and the forced swim test, respectively. Expression of cytokines and IDO mRNA was measured by real-time RT-PCR and cytokine protein was measured by enzyme-linked immunosorbent assays (ELISAs. Enzymatic activity of IDO was estimated as the amount of kynurenine produced from tryptophan as determined by high pressure liquid chromatography (HPLC with electrochemical detection. Results Intracerebroventricular (i.c.v. administration of LPS (100 ng increased steady-state transcripts of TNFα, IL-6 and the inducible isoform of nitric oxide synthase (iNOS in the hippocampus in the absence of any change in IFNγ mRNA. LPS also increased IDO expression and induced depressive-like behavior, as measured by increased duration of immobility in the forced swim test. The regulation of IDO expression was investigated using in situ organotypic hippocampal slice cultures (OHSCs derived from brains of newborn C57BL/6J mice. In accordance with the in vivo data, addition of LPS (10 ng/ml to the medium of OHSCs induced steady-state expression of mRNA transcripts for IDO that peaked at 6 h and translated into increased IDO enzymatic activity within 8 h post-LPS. This activation of IDO by direct application of LPS was preceded by synthesis and secretion of TNFα and IL-6 protein and activation of iNOS while IFNγ expression was undetectable. Conclusion These data establish that activation of the innate immune system in the brain is sufficient to activate IDO and induce

  11. Quantitative assessment of hemodynamic and structural characteristics of in vivo brain tissue using total diffuse reflectance spectrum measured in a non-contact fashion.

    Science.gov (United States)

    Song, Yinchen; Garcia, Sarahy; Frometa, Yisel; Ramella-Roman, Jessica C; Soltani, Mohammad; Almadi, Mohamed; Riera, Jorge J; Lin, Wei-Chiang

    2017-01-01

    Here we present a new methodology that investigates the intrinsic structural and hemodynamic characteristics of in vivo brain tissue, in a non-contact fashion, and can be easily incorporated in an intra-operative environment. Within this methodology, relative total diffuse reflectance spectra (R TD (λ)) were acquired from targets using a hybrid spectroscopy imaging system. A spectral interpretation algorithm was subsequently applied to R TD (λ) to retrieve optical properties related to the compositional and structural characteristics of each target. Estimation errors of the proposed methodology were computationally evaluated using a Monte Carlo simulation model for photon migration under various conditions. It was discovered that this new methodology could handle moderate noise and achieve very high accuracy, but only if the refractive index of the target is known. The accuracy of the technique was also validated using a series of tissue phantom studies, and consistent and accurate estimates of μ s '(λ)/μ a (λ) were obtained from all the phantoms tested. Finally, a small-scale animal study was conducted to demonstrate the clinical utility of the reported method, wherein a forepaw stimulation model was utilized to induce transient hemodynamic responses in somatosensory cortices. With this approach, significant stimulation-related changes (p < 0.001) in cortical hemodynamic and structural characteristics were successfully measured.

  12. In vivo measurements of brain glucose transport using the reversible michaelis-menten model and simultaneous measurements of cerebral blood flow changes during hypoglycemia

    OpenAIRE

    Choi, I.-Y.; Lee, S.-P.; Kim, S.-G.; Gruetter, R.

    2001-01-01

    Glucose is the major substrate that sustains normal brain function. When the brain glucose concentration approaches zero, glucose transport across the blood-brain barrier becomes rate limiting for metabolism during, for example, increased metabolic activity and hypoglycemia. Steady-state brain glucose concentrations in α-chloralose anesthetized rats were measured noninvasively as a function of plasma glucose. The relation between brain and plasma glucose was linear at 4.5 to 30 mmol/L plasma ...

  13. Specific in vivo binding in the rat brain of [{sup 18}F]RP 62203: A selective 5-HT{sub 2A} receptor radioligand for positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Besret, Laurent; Dauphin, Francois; Huard, Cecile; Lasne, Marie-Claire; Vivet, Richard; Mickala, Patrick; Barbelivien, Alexandra; Baron, Jean-Claude

    1996-02-01

    In vivo pharmacokinetic and brain binding characteristics of [{sup 18}F]RP 62203, a selective high-affinity serotonergic 5-HT{sub 2A} receptor antagonist, were assessed in the rat following intravenous injection of trace amount of the radioligand. The radioactive distribution profile observed in the brain 60 min after injection was characterized by greater than fourfold higher uptake in neocortex as compared to cerebellum (0.38 {+-} 0.07% injected dose/g, % ID/g and 0.08 {+-} 0.01 ID/g, respectively), consistent with in vivo specific binding to the 5-HT{sub 2A} receptor. Furthermore, specific [{sup 18}F]RP 62203 binding significantly correlated with the reported in vitro distribution of 5-HT{sub 2A} receptors, but not with known concentration profiles of dopaminergic D{sub 2} or adrenergic {alpha}{sub 1} receptors. Finally, detectable specific binding was abolished by pretreatment with large doses of ritanserin, a selective 5-HT{sub 2A} antagonist, which resulted in uniform uptakes across cortical, striatal and cerebellar tissues. Thus, [{sup 18}F]RP 62203 appears to be a promising selective tool to visualize and quantify 5-HT{sub 2A} brain receptors in vivo with positron emission tomography.

  14. Occupational Health

    Science.gov (United States)

    Occupational health problems occur at work or because of the kind of work you do. These problems can include ... by exposure to radiation Exposure to germs in health care settings Good job safety and prevention practices ...

  15. Occupational cancer

    International Nuclear Information System (INIS)

    Choril, A.C.; McCracken, W.J.; Dowd, E.C.; Stewart, Charles; Burton, D.F.; Dyer, D.W.

    1981-01-01

    This paper reviews the experience of the Workmen's Compensation Board of Ontario in identifying cases of cancer that could be attributed to occupational hazards. Workers' claims for compensation are allowed if there is reasonable medical evidence that their cancer was caused by exposure to risk factors associated with their occupation. Details of the types of cancers associated with specific carcinogens or fields of employment are discussed. About 50% of the cases were related to exposure in particular industrial operations that functioned for relatively brief periods. The number of deaths from cancer identified as being caused by occupational factors is compared with the total for cancer from all causes in Ontario during the period 1971 through 1975. Although all workers eligible for compensation may not have been identified, the data suggest that less than 1% is presently caused by occupational factors

  16. Occupational Cancer

    Science.gov (United States)

    ... November 3, 2015 Content source: National Institute for Occupational Safety and Health Division of Surveillance, Hazard Evaluations, and Field Studies ... Fear Act OIG 1600 Clifton Road Atlanta , GA 30329-4027 ...

  17. Occupational health

    CERN Document Server

    Fingret, Dr Ann

    2013-01-01

    Offers a comprehensive view of health and safety issues at work. An invaluable resource for managers, personnel professionals and occupational health practitioners. Recommended by the Institute of Personnel Management.

  18. Occupational cancer

    International Nuclear Information System (INIS)

    Nelson, N.

    1987-01-01

    Cancer resulting from occupational exposure is now receiving major attention, focusing on identification, regulation, and control of cancer-causing agents. Such cancer can result from exposure to chemicals and ionizing and nonionizing radiation. Extended exposure (often years) and an extended latent period of perhaps decades may intervene before tumor appearance. Although the actual extent of occupational cancer is in debate, estimates have ranged from 4 to 15 per cent of all cancer

  19. Occupational health

    OpenAIRE

    Coosemans, R.

    1997-01-01

    Health at work and healthy work environments are among the most valuable assets of individuals, communities and countries. Nowadays, new broader approach is promoted, recognizing the fact that occupational health is a key, but not a unique element of workers’ health. Workers health is a public health approach to resolving the health problems of working populations including all determinants of health recognized as targets of risk management. It focuses on primary prevention of occupational an...

  20. Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo.

    Science.gov (United States)

    Itoh, Yoshiaki; Esaki, Takanori; Shimoji, Kazuaki; Cook, Michelle; Law, Mona J; Kaufman, Elaine; Sokoloff, Louis

    2003-04-15

    Neuronal cultures in vitro readily oxidized both D-[(14)C]glucose and l-[(14)C]lactate to (14)CO(2), whereas astroglial cultures oxidized both substrates sparingly and metabolized glucose predominantly to lactate and released it into the medium. [(14)C]Glucose oxidation to (14)CO(2) varied inversely with unlabeled lactate concentration in the medium, particularly in neurons, and increased progressively with decreasing lactate concentration. Adding unlabeled glucose to the medium inhibited [(14)C]lactate oxidation to (14)CO(2) only in astroglia but not in neurons, indicating a kinetic preference in neurons for oxidation of extracellular lactate over intracellular pyruvatelactate produced by glycolysis. Protein kinase-catalyzed phosphorylation inactivates pyruvate dehydrogenase (PDH), which regulates pyruvate entry into the tricarboxylic acid cycle. Dichloroacetate inhibits this kinase, thus enhancing PDH activity. In vitro dichloroacetate stimulated glucose and lactate oxidation to CO(2) and reduced lactate release mainly in astroglia, indicating that limitations in glucose and lactate oxidation by astroglia may be due to a greater balance of PDH toward the inactive form. To assess the significance of astroglial export of lactate to neurons in vivo, we attempted to diminish this traffic in rats by administering dichloroacetate (50 mgkg) intravenously to stimulate astroglial lactate oxidation and then examined the effects on baseline and functionally activated local cerebral glucose utilization (lCMR(glc)). Dichloroacetate raised baseline lCMR(glc) throughout the brain and decreased the percent increases in lCMR(glc) evoked by functional activation. These studies provide evidence in support of the compartmentalization of glucose metabolism between astroglia and neurons but indicate that the compartmentalization may be neither complete nor entirely obligatory.

  1. Role of brain-derived neurotrophic factor and nerve growth factor in the regulation of Neuropeptide W in vitro and in vivo.

    Science.gov (United States)

    Wang, Rikang; Yan, Fengxia; Liao, Rifang; Wan, Pei; Little, Peter J; Zheng, Wenhua

    2017-05-15

    Nerve growth factor (NGF) and Brain-derived neurotrophic factor (BDNF) are neurotrophic factors involved in the growth, survival and functioning of neurons. In addition, a possible role of neurotrophins, particularly BDNF, in HPA axis hyperactivation has recently been proposed. Neuropeptide W (NPW) is an endogenous peptide ligand for the GPR7 and GPR8 and a stress mediator in the hypothalamus. It activates the HPA axis by working on hypothalamic corticotrophin-releasing hormone (CRH). No information is available about the interrelationships between neurotrophines like NGF/BDNF and NPW. We studied the effect and underlying mechanisms of NGF/BDNF on the production of NPW in PC12 cells and hypothalamus. NGF time- and concentration-dependently stimulated the expression of NPW in PC12 cells. The effect of NGF was blocked by the inhibition of PI3K/Akt signal pathway with specific inhibitors for PI3K or AktsiRNA for Akt while inhibition of ERK pathway had no effect. Moreover, BDNF concentration-dependently induced the expression of NPW mRNA and decreased the expression of NPY mRNA in primary cultured hypothalamic neurons which was also blocked by a PI3K kinase inhibitor. Finally, in vivo study showed that exogenous BDNF injected icv increased NPW production in the hypothalamus and this effect was reversed by a PI3 kinase inhibitor. These results and the fact that BDNF was able to stimulate the expression of CRH demonstrated that neurotrophines can modulate the expression of NPW in neuronal cells via the PI3K/Akt pathway and suggest that BDNF might be involved in functions of the HPA axis, at least in part by modulating the expression of NPW/NPY and CRH. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Effects of hepatic ischemia-reperfusion injury on the P-glycoprotein activity at the liver canalicular membrane and blood-brain barrier determined by in vivo administration of rhodamine 123 in rats.

    Science.gov (United States)

    Miah, Mohammad K; Shaik, Imam H; Bickel, Ulrich; Mehvar, Reza

    2014-04-01

    To investigate the effects of normothermic hepatic ischemia-reperfusion (IR) injury on the activity of P-glycoprotein (P-gp) in the liver and at the blood-brain barrier (BBB) of rats using rhodamine 123 (RH-123) as an in vivo marker. Rats were subjected to 90 min of partial ischemia or sham surgery, followed by 12 or 24 h of reperfusion. Following intravenous injection, the concentrations of RH-123 in blood, bile, brain, and liver were used for pharmacokinetic calculations. The protein levels of P-gp and some other transporters in the liver and brain were also determined by Western blot analysis. P-gp protein levels at the liver canalicular membrane were increased by twofold after 24 h of reperfusion. However, the biliary excretion of RH-123 was reduced in these rats by 26%, presumably due to IR-induced reductions in the liver uptake of the marker and hepatic ATP concentrations. At the BBB, a 24% overexpression of P-gp in the 24-h IR animals was associated with a 30% decrease in the apparent brain uptake clearance of RH-123. The pharmacokinetics or brain distribution of RH-123 was not affected by the 12-h IR injury. Hepatic IR injury may alter the peripheral pharmacokinetics and brain distribution of drugs that are transported by P-gp and possibly other transporters.

  3. In vivo 13C MRS in the mouse brain at 14.1 Tesla and metabolic flux quantification under infusion of [1,6-13C2]glucose.

    Science.gov (United States)

    Lai, Marta; Lanz, Bernard; Poitry-Yamate, Carole; Romero, Jackeline F; Berset, Corina M; Cudalbu, Cristina; Gruetter, Rolf

    2017-01-01

    In vivo 13 C magnetic resonance spectroscopy (MRS) enables the investigation of cerebral metabolic compartmentation while, e.g. infusing 13 C-labeled glucose. Metabolic flux analysis of 13 C turnover previously yielded quantitative information of glutamate and glutamine metabolism in humans and rats, while the application to in vivo mouse brain remains exceedingly challenging. In the present study, 13 C direct detection at 14.1 T provided highly resolved in vivo spectra of the mouse brain while infusing [1,6- 13 C 2 ]glucose for up to 5 h. 13 C incorporation to glutamate and glutamine C4, C3, and C2 and aspartate C3 were detected dynamically and fitted to a two-compartment model: flux estimation of neuron-glial metabolism included tricarboxylic acid cycle (TCA) flux in astrocytes (V g  = 0.16 ± 0.03 µmol/g/min) and neurons (V TCA n  = 0.56 ± 0.03 µmol/g/min), pyruvate carboxylase activity (V PC  = 0.041 ± 0.003 µmol/g/min) and neurotransmission rate (V NT  = 0.084 ± 0.008 µmol/g/min), resulting in a cerebral metabolic rate of glucose (CMR glc ) of 0.38 ± 0.02 µmol/g/min, in excellent agreement with that determined with concomitant 18 F-fluorodeoxyglucose positron emission tomography ( 18 FDG PET).We conclude that modeling of neuron-glial metabolism in vivo is accessible in the mouse brain from 13 C direct detection with an unprecedented spatial resolution under [1,6- 13 C 2 ]glucose infusion.

  4. In vivo imaging of brain estrogen receptors in rats : a 16α-18F-fluoro-17β-estradiol PET study

    NARCIS (Netherlands)

    Khayum, Mohammed A; de Vries, Erik F J; Glaudemans, Andor W J M; Dierckx, Rudi A J O; Doorduin, Janine

    UNLABELLED: The steroid hormone estrogen is important for brain functioning and is thought to be involved in brain diseases, such as Alzheimer disease and depression. The action of estrogen is mediated by estrogen receptors (ERs). To understand the role of estrogens in brain functioning, it is

  5. Comparison of in vivo and ex vivo imaging of the microvasculature with 2-photon fluorescence microscopy

    Science.gov (United States)

    Steinman, Joe; Koletar, Margaret; Stefanovic, Bojana; Sled, John G.

    2016-03-01

    This study evaluates 2-Photon fluorescence microscopy of in vivo and ex vivo cleared samples for visualizing cortical vasculature. Four mice brains were imaged with in vivo 2PFM. Mice were then perfused with a FITC gel and cleared in fructose. The same regions imaged in vivo were imaged ex vivo. Vessels were segmented automatically in both images using an in-house developed algorithm that accounts for the anisotropic and spatially varying PSF ex vivo. Through non-linear warping, the ex vivo image and tracing were aligned to the in vivo image. The corresponding vessels were identified through a local search algorithm. This enabled comparison of identical vessels in vivo/ex vivo. A similar process was conducted on the in vivo tracing to determine the percentage of vessels perfused. Of all the vessels identified over the four brains in vivo, 98% were present ex vivo. There was a trend towards reduced vessel diameter ex vivo by 12.7%, and the shrinkage varied between specimens (0% to 26%). Large diameter surface vessels, through a process termed 'shadowing', attenuated in vivo signal from deeper cortical vessels by 40% at 300 μm below the cortical surface, which does not occur ex vivo. In summary, though there is a mean diameter shrinkage ex vivo, ex vivo imaging has a reduced shadowing artifact. Additionally, since imaging depths are only limited by the working distance of the microscope objective, ex vivo imaging is more suitable for imaging large portions of the brain.

  6. In vivo binding and autoradiographic imaging of (+)-3-[125I]Iodo-MK-801 to the NMDA receptor-channel complex in rat brain

    International Nuclear Information System (INIS)

    Gibson, R.E.; Burns, H.D.; Thorpe, H.H.; Waisi Eng; Ransom, R.; Solomon, H.

    1992-01-01

    Radioiodinated (+)-3-Iodo-MK-801 is a high affinity radioligand for the N-methyl-D-aspartate (NMDA) receptor-channel complex. We have demonstrated in vivo localization in the CNS of rat which is stereoselective and blocked by coinjection of unlabeled MK-801. Autoradiography indicates localization in vivo which is in concordance with in vitro autoradiographic studies. These results indicate that radioiodinated (+)-3-Iodo-MK-801 is a useful probe for in vitro and in vivo autoradiographic studies and suggest that radioligands for the NMDA receptor may be developed which will provide in vivo images of receptor distribution in man. (author)

  7. Reduction of Endogenous Melatonin Accelerates Cognitive Decline in Mice in a Simulated Occupational Formaldehyde Exposure Environment

    Directory of Open Access Journals (Sweden)

    Yufei Mei

    2016-02-01

    Full Text Available Individuals afflicted with occupational formaldehyde (FA exposure often suffer from abnormal behaviors such as aggression, depression, anxiety, sleep disorders, and in particular, cognitive impairments. Coincidentally, clinical patients with melatonin (MT deficiency also complain of cognitive problems associated with the above mental disorders. Whether and how FA affects endogenous MT metabolism and induces cognitive decline need to be elucidated. To mimic occupational FA exposure environment, 16 healthy adult male mice were exposed to gaseous FA (3 mg/m3 for 7 consecutive days. Results showed that FA exposure impaired spatial memory associated with hippocampal neuronal death. Biochemical analysis revealed that FA exposure elicited an intensive oxidative stress by reducing systemic glutathione levels, in particular, decreasing brain MT concentrations. Inversely, intraperitoneal injection of MT markedly attenuated FA-induced hippocampal neuronal death, restored brain MT levels, and reversed memory decline. At tissue levels, injection of FA into the hippocampus distinctly reduced brain MT concentrations. Furthermore, at cellular and molecular levels, we found that FA directly inactivated MT in vitro and in vivo. These findings suggest that MT supplementation contributes to the rescue of cognitive decline, and may alleviate mental disorders in the occupational FA-exposed human populations.

  8. Modification of the striatal dopaminergic neuron system by carbon monoxide exposure in free-moving rats, as determined by in vivo brain microdialysis

    Energy Technology Data Exchange (ETDEWEB)

    Hara, Shuichi; Kurosaki, Kunihiko; Kuriiwa, Fumi; Endo, Takahiko [Department of Forensic Medicine, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402 (Japan); Mukai, Toshiji [Department of Legal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-0015 (Japan)

    2002-10-01

    Acute carbon monoxide (CO) intoxication in humans results in motor deficits, which resemble those in Parkinson's disease, suggesting possible disturbance of the central dopaminergic (DAergic) neuronal system by CO exposure. In the present study, therefore, we explored the effects of CO exposure on the DAergic neuronal system in the striatum of freely moving rats by means of in vivo brain microdialysis. Exposure of rats to CO (up to 0.3%) for 40 min caused an increase in extracellular dopamine (DA) levels and a decrease in extracellular levels of its major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum depending on the CO concentration. Reoxygenation following termination of the CO exposure resulted in a decline of DA to the control level and an overshoot in the recovery of DOPAC and HVA to levels higher than the control. A monoamine oxidase type A (MAO-A) inhibitor, clorgyline, significantly potentiated the CO-induced increase in DA and completely abolished the subsequent overshoot in the recovery of DOPAC and HVA. Tetrodotoxin, a Na{sup +} channel blocker, completely abolished both the CO-induced increase in DA and the overshoot of DOPAC and HVA. A DA uptake inhibitor, nomifensine, strongly potentiated the CO-induced increase in DA without affecting the subsequent overshoot of DOPAC and HVA. Clorgyline further potentiated the effect of nomifensine on the CO-induced increase in DA, although a slight overshoot of DOPAC and HVA appeared. These findings suggest that (1) CO exposure may stimulate Na{sup +}-dependent DA release in addition to suppressing DA metabolism, resulting in a marked increase in extracellular DA in rat striatum, and (2) CO withdrawal and subsequent reoxygenation may enhance the oxidative metabolism, preferentially mediated by MAO-A, of the increased extracellular DA. In the light of the neurotoxicity of DA per se and reactive substances, such as quinones and activated oxygen species

  9. The bubble-dependent mechanism of FUS-induced blood-brain barrier opening in mice and in monkeys in vivo

    Science.gov (United States)

    Tung, Yao-Sheng; Marquet, Fabrice; Vlachos, Fotios; Feshitan, Jameel A.; Borden, Mark A.; Konofagou, Elisa E.

    2012-10-01

    The blood-brain barrier (BBB) prevents most neurological drugs from traversing from the cerebral microvasculature into the brain parenchyma. Previous studies have shown that the presence of bubbles in an acoustic field temporarily opens the BBB. The BBB opening pressure threshold was previously identified to lie between 0.30 and 0.46 MPa in the case of the smaller bubbles and between 0.15 and 0.30 MPa in the larger bubble case. However, the physical effects responsible for BBB opening remain unknown. In addition, the noninvasive in vivo cavitation detection with mono-dispersed microbubbles has not been studied as of yet. The purpose of this study is to unveil the physical mechanism of the FUS-induced BBB opening with monodispersed microbubbles. Lipid-shelled microbubbles with three different diameters (1-2, 4-5 and 6-8 μm) were manufactured in-house and size-isolated using differential centrifugation. Sixty-seven (n=67) mice were each injected intravenously with bubbles of either 1-2, 4-5 or 6-8 μm in diameter and the concentration of 107 numbers/mL. The right hippocampus of each mouse was then sonicated using focused ultrasound (1.5 MHz frequency; 100 cycles (67 μs) pulse length; 10 Hz pulse repetition frequency; 1 minute sonication duration) while the left hippocampus served as the control. A 10-MHz transducer was used as a passive cavitation detector (PCD) to determine the threshold of inertial cavitation (IC). Each mouse was sonicated at a specific acoustic peak-rarefactional pressure at 0.15, 0.30, 0.45 or 0.60 MPa in order to identify the threshold of BBB opening and IC. T1-weighted MRI was used to verify the BBB opening and spectrograms were generated in order to detect the IC onset and duration. Our results suggest that the BBB opens as a result of nonlinear (harmonic) bubble oscillation when the bubble diameter is similar to the capillary diameter and with inertial cavitation when it is not. The bubble may thus have to be in contact with the capillary

  10. Occupational hazards

    OpenAIRE

    Paz-Fuchs, Amir; Ronen, Yaël

    2012-01-01

    This article provides an analysis and a critique of the law governing the employment relationship between Israeli employers and Palestinian employees in industries operating in the West Bank. \\ud \\ud Through an analysis of Israeli jurisprudence it highlights the intersection among different areas of law: choice of law, public international law (in particular the law of occupation), and labor law. The article explores the tensions that this intersection creates: first, between the importance t...

  11. "Heart-cut" bidimensional achiral-chiral liquid chromatography applied to the evaluation of stereoselective metabolism, in vivo biological activity and brain response to chiral drug candidates targeting the central nervous system.

    Science.gov (United States)

    Battisti, Umberto M; Citti, Cinzia; Larini, Martina; Ciccarella, Giuseppe; Stasiak, Natalia; Troisi, Luigino; Braghiroli, Daniela; Parenti, Carlo; Zoli, Michele; Cannazza, Giuseppe

    2016-04-22

    A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug

  12. Who among patients with acquired brain injury returned to work after occupational rehabilitation? The rapid-return-to-work-cohort-study.

    Science.gov (United States)

    Aas, Randi Wågø; Haveraaen, Lise Aasen; Brouwers, Evelien P M; Skarpaas, Lisebet Skeie

    2017-07-20

    Acquired brain injury (ABI) is known to be severely disabling. On average, 40% of employees return to work (RTW) within two years after injury. There is, however, limited research on what might contribute to successful RTW. To examine factors that might impact the time-to first RTW for patients with ABI, participating in a RTW-program. The study was designed as a cohort study of patients on sick leave due to mild or moderate ABI (n = 137). The mean age of the patients was 51 years, and 58% were men. The most common diagnoses were stroke (75%) and traumatic brain injury (12%). Data were collected through questionnaires, and combined with register data on sickness absence. Survival analyses were used to analyse the effect of different variables on time to first RTW (full or partial), at one- and two-year follow-up. Generally, women (HR = 0.447; CI: 0.239-0.283) had higher RTW-rates than men, and patients with non-comorbid impairments returned to work earlier than patients with multiple impairments. Although not statistically significant, receiving individual consultations and participating in group-sessions were generally associated with a delayed RTW at both follow-up-times. The only service-related factor significantly associated with delayed RTW was meetings with the social insurance office (HR = 0.522; CI: 0.282-0.965), and only at one-year follow-up. Women and patients with non-comorbid impairments returned to work earlier than men and patients with multiple impairments. There seems to be an association between intense and long-lasting participation in the RTW program and prolonged time-to first-RTW, even after controlling for level of cognitive impairments and comorbidity. Implications for Rehabilitation Acquired brain injury (ABI) is known to be severely disabling, and persons with ABI often experience difficulties in regard to returning to work. This study provides information on prognostic factors that might contribute to return to work (RTW

  13. Occupation: nurse; occupational hazard: radiation

    International Nuclear Information System (INIS)

    Nickson, K.

    1984-01-01

    The work of the occupational health nurses at the Pickering Generating Station is described. A staff of two nurses teach first aid and safety, practice an emergency plan, and monitor personnel for minimum health standards for radiation workers. Special attention is paid to problems which might be aggravated by radiation, such as skin complaints, respiratory diseases, emotional stability, or phobias regarding heights, plastic suits, or radiation itself. Procedures used in treating contaminated personnel are outlined

  14. Occupation: nurse; occupational hazard: radiation

    Energy Technology Data Exchange (ETDEWEB)

    Nickson, K

    1984-03-01

    The work of the occupational health nurses at the Pickering Generating Station is described. A staff of two nurses teach first aid and safety, practice an emergency plan, and monitor personnel for minimum health standards for radiation workers. Special attention is paid to problems which might be aggravated by radiation, such as skin complaints, respiratory diseases, emotional stability, or phobias regarding heights, plastic suits, or radiation itself. Procedures used in treating contaminated personnel are outlined.

  15. Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model.

    Directory of Open Access Journals (Sweden)

    Takashi Machida

    Full Text Available Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood-brain barrier (BBB exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the central nervous system (CNS. We hypothesized that brain pericytes respond to increased brain thrombin levels in diabetes, leading to BBB dysfunction and diabetic CNS complications. Mice were fed a high-fat diet (HFD for 2 or 8 weeks to induce obesity. Transport of i.v.-administered sodium fluorescein and 125I-thrombin across the BBB were measured. We evaluated brain endothelial permeability and expression of tight junction proteins in the presence of thrombin-treated brain pericytes using a BBB model of co-cultured rat brain endothelial cells and pericytes. Mice fed a HFD for 8 weeks showed both increased weight gain and impaired glucose tolerance. In parallel, the brain influx rate of sodium fluorescein was significantly greater than that in mice fed a normal diet. HFD feeding inhibited the decline in brain thrombin levels occurring during 6 weeks of feeding. In the HFD fed mice, plasma thrombin levels were significantly increased, by up to 22%. 125I-thrombin was transported across the BBB in normal mice after i.v. injection, with uptake further enhanced by co-injection of unlabeled thrombin. Thrombin-treated brain pericytes increased brain endothelial permeability and caused decreased expression of zona occludens-1 (ZO-1 and occludin and morphological disorganization of ZO-1. Thrombin also increased mRNA expression of interleukin-1β and 6 and tumor necrosis factor-α in brain pericytes. Thrombin can be transported from circulating blood through the BBB, maintaining constant levels in the brain, where it can stimulate pericytes to induce BBB dysfunction. Thus, the brain pericyte-thrombin interaction may play a key role in causing BBB dysfunction in

  16. Conjugates of Superoxide Dismutase 1 with Amphiphilic Poly(2-oxazoline) Block Copolymers for Enhanced Brain Delivery: Synthesis, Characterization and Evaluation in Vitro and in Vivo

    KAUST Repository

    Tong, Jing; Yi, Xiang; Luxenhofer, Robert; Banks, William A.; Jordan, Rainer; Zimmerman, Matthew C.; Kabanov, Alexander V.

    2013-01-01

    Superoxide dismutase 1 (SOD1) efficiently catalyzes dismutation of superoxide, but its poor delivery to the target sites in the body, such as brain, hinders its use as a therapeutic agent for superoxide-associated disorders. Here to enhance

  17. Robust motion correction and outlier rejection of in vivo functional MR images of the fetal brain and placenta during maternal hyperoxia

    OpenAIRE

    You, Wonsang; Serag, Ahmed; Evangelou, Iordanis E.; Andescavage, Nickie; Limperopoulos, Catherine

    2017-01-01

    Subject motion is a major challenge in functional magnetic resonance imaging studies (fMRI) of the fetal brain and placenta during maternal hyperoxia. We propose a motion correction and volume outlier rejection method for the correction of severe motion artifacts in both fetal brain and placenta. The method is optimized to the experimental design by processing different phases of acquisition separately. It also automatically excludes high-motion volumes and all the missing data are regressed ...

  18. Robust motion correction and outlier rejection of in vivo functional MR images of the fetal brain and placenta during maternal hyperoxia

    OpenAIRE

    You, Wonsang; Serag, Ahmed; Evangelou, Iordanis E.; Andescavage, Nickie; Limperopoulos, Catherine

    2015-01-01

    Subject motion is a major challenge in functional magnetic resonance imaging studies (fMRI) of the fetal brain and placenta during maternal hyperoxia. We propose a motion correction and volume outlier rejection method for the correction of severe motion artifacts in both fetal brain and placenta. The method is optimized to the experimental design by processing different phases of acquisition separately. It also automatically excludes high-motion volumes and all the missing data are regressed ...

  19. Occupational physiology

    CERN Document Server

    Toomingas, Allan; Tornqvist, Ewa Wigaeus

    2011-01-01

    In a clear and accessible presentation, Occupational Physiology focuses on important issues in the modern working world. Exploring major public health problems-such as musculoskeletal disorders and stress-this book explains connections between work, well-being, and health based on up-to-date research in the field. It provides useful methods for risk assessment and guidelines on arranging a good working life from the perspective of the working individual, the company, and society as a whole.The book focuses on common, stressful situations in different professions. Reviewing bodily demands and r

  20. In vivo brain dopaminergic receptor site mapping using 75Se-labeled pergolide analogs: the effects of various dopamine receptor agonists and antagonists

    International Nuclear Information System (INIS)

    Weaver, A.

    1986-01-01

    Perogolide mesylate is a new synthetic ergoline derivative which is reported to possess agonistic activity at central dopamine receptor sites in the brain. The authors have synthesized a [ 75 Se]-radiolabeled pergolide mesylate derivative, [ 75 Se]-pergolide tartrate, which, after i.v. administration to mature male rats, showed a time course differentiation in the uptake of this radiolabeled compound in isolated peripheral and central (brain) tissues that are known to be rich in dopamine receptor sites. Further studies were conducted in which the animals were preexposed to the dopamine receptor agonist SKF-38393, as well as the dopamine receptor antagonists (+)-butaclamol, (-)-butaclamol, (+/-)-butaclamol and (-)-chloroethylnorapomorphine, to substantiate the specific peripheral and central localization patterns of [ 75 Se]-pergolide tartrate. Further investigations were also conducted in which the animals received an i.v. administration of N-isopropyl-l-123-p-iodoamphetamine ([ 123 I]-iodoamphetamine). However, [ 123 I]-iodoamphetamine did not demonstrate a specific affinity for any type of receptor site in the brain. These investigations further substantiated the fact that [ 75 Se]-pergolide tartrate does cross the blood-brain barrier is quickly localized at specific dopamine receptor sites in the intact rat brain and that this localization pattern can be affected by preexposure to different dopamine receptor agonists and antagonists. Therefore, these investigations provided further evidence that [ 75 Se]-pergolide tartrate and other radiolabeled ergoline analogs might be useful as brain dopamine receptor localization radiopharmaceuticals

  1. Brain refractive index measured in vivo with high-NA defocus-corrected full-field OCT and consequences for two-photon microscopy.

    Science.gov (United States)

    Binding, Jonas; Ben Arous, Juliette; Léger, Jean-François; Gigan, Sylvain; Boccara, Claude; Bourdieu, Laurent

    2011-03-14

    Two-photon laser scanning microscopy (2PLSM) is an important tool for in vivo tissue imaging with sub-cellular resolution, but the penetration depth of current systems is potentially limited by sample-induced optical aberrations. To quantify these, we measured the refractive index n' in the somatosensory cortex of 7 rats in vivo using defocus optimization in full-field optical coherence tomography (ff-OCT). We found n' to be independent of imaging depth or rat age. From these measurements, we calculated that two-photon imaging beyond 200 µm into the cortex is limited by spherical aberration, indicating that adaptive optics will improve imaging depth.

  2. Main effect and interactions of brain regions and gender in the calculation of volumetric asymmetry indices in healthy human brains: ANCOVA analyses of in vivo 3T MRI data.

    Science.gov (United States)

    Roldan-Valadez, Ernesto; Rios, Camilo; Suarez-May, Marcela A; Favila, Rafel; Aguilar-Castañeda, Erika

    2013-12-01

    Macroanatomical right-left hemispheric differences in the brain are termed asymmetries, although there is no clear information on the global influence of gender and brain-regions. The aim of this study was to evaluate the main effects and interactions of these variables on the measurement of volumetric asymmetry indices (VAIs). Forty-seven healthy young-adult volunteers (23 males, 24 females) agreed to undergo brain magnetic resonance imaging in a 3T scanner. Image post processing using voxel-based volumetry allowed the calculation of 54 VAIs from the frontal, temporal, parietal and occipital lobes, limbic system, basal ganglia, and cerebellum for each cerebral hemisphere. Multivariate ANCOVA analysis calculated the main effects and interactions on VAIs of gender and brain regions controlling the effect of age. The only significant finding was the main effect of brain regions (F (6, 9373.605) 44.369, P gender and brain regions (F (6, 50.517) .239, P = .964). Volumetric asymmetries are present across all brain regions, with larger values found in the limbic system and parietal lobe. The absence of a significant influence of gender and age in the evaluation of the numerous measurements generated by multivariate analyses in this study should not discourage researchers to report and interpret similar results, as this topic still deserves further assessment. Copyright © 2013 Wiley Periodicals, Inc.

  3. Different early effect of irradiation in brain and small cell lung cancer examined by in vivo 31P-magnetic resonance spectroscopy

    DEFF Research Database (Denmark)

    Kristjansen, P E; Pedersen, A G; Quistorff, B

    1992-01-01

    Early effects of irradiation were evaluated by non-invasive in vivo 31P-magnetic resonance spectroscopy (31P-MRS) of two small cell lung cancer (SCLC) tumor lines CPH SCCL 54A and 54B, in nude mice. The tumors were originally derived from the same patient and have similar morphology and growth...

  4. Unique Distribution of Aromatase in the Human Brain: In Vivo Studies With PET and (N-Methyl-11C)Vorozole

    International Nuclear Information System (INIS)

    Biegon, A.; Kim, S.W.; Alexoff, D.; Millard, J.; Carter, P.; Hubbard, B.; King, P.; Logan, J.; Muench, L.; Pareto, D.; Schlyer, D.; Shea, C.; Telang, F.; Wang, G.-J.; Xu, Y.; Fowler, J.

    2010-01-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor (N-methyl- 11 C)vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V T ) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced VT in all regions, though the size of the reduction was region-dependent, ranging from ∼70% blocking in thalamus andpreoptic area to ∼10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  5. Unique Distribution of Aromatase in the Human Brain: In Vivo Studies With PET and [N-Methyl-11C]Vorozole

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Biegon, A.; Kim, S.W.; Alexoff, D.; Millard, J.; Carter, P.; Hubbard, B.; King, P.; Logan, J.; Muench, L.; Pareto, D.; Schlyer, D.; Shea, C.; Telang, F.; Wang, G.-J.; Xu, Y.; Fowler, J.

    2010-10-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-{sup 11}C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V{sub T}) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced VT in all regions, though the size of the reduction was region-dependent, ranging from {approx}70% blocking in thalamus andpreoptic area to {approx}10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  6. Structural and metabolic changes in the traumatically injured rat brain. High-resolution in vivo proton magnetic resonance spectroscopy at 7 T

    International Nuclear Information System (INIS)

    Li, Jing; Zhao, Can; Rao, Jia-Sheng; Yang, Fei-Xiang; Yang, Zhao-Yang; Wang, Zhan-Jing; Lei, Jian-Feng; Li, Xiao-Guang

    2017-01-01

    The understanding of microstructural and metabolic changes in the post-traumatic brain injury is the key to brain damage suppression and repair in clinics. Ten female Wistar rats were traumatically injured in the brain CA1 region and above the cortex. Next, diffusion tensor magnetic resonance imaging (DTI) and proton magnetic resonance spectroscopy ( 1 H MRS) were used to analyze the microstructural and metabolic changes in the brain within the following 2 weeks. Anisotropy fraction (FA) and axial diffusivity (AD) of the corpus callosum (CC) began to decrease significantly at day 1, whereas radial diffusivity (RD) significantly increased immediately after injury, reflecting the loss of white matter integrity. Compared with day 3, RD decreased significantly at day 7, implicating the angioedema reduction. In the hippocampus, FA significantly increased at day 7; the choline-containing compounds (Cho) and myo-inositol (MI) remarkably increased at day 7 compared with those at day 3, indicating the proliferation of astrocytes and radial glial cells after day 7. No significant differences between DTI and 1 H MRS parameters were observed between day 1 and day 3. Day 1-3 after traumatic brain injury (TBI) may serve as a relatively appropriate time window for treatment planning and the following nerve repair. (orig.)

  7. Unique distribution of aromatase in the human brain: in vivo studies with PET and [N-methyl-11C]vorozole.

    Science.gov (United States)

    Biegon, Anat; Kim, Sung Won; Alexoff, David L; Jayne, Millard; Carter, Pauline; Hubbard, Barbara; King, Payton; Logan, Jean; Muench, Lisa; Pareto, Deborah; Schlyer, David; Shea, Colleen; Telang, Frank; Wang, Gene-Jack; Xu, Youwen; Fowler, Joanna S

    2010-11-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-(11)C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V(T)) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced V(T) in all regions, though the size of the reduction was region-dependent, ranging from ∼70% blocking in thalamus andpreoptic area to ∼10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  8. Structural and metabolic changes in the traumatically injured rat brain. High-resolution in vivo proton magnetic resonance spectroscopy at 7 T

    Energy Technology Data Exchange (ETDEWEB)

    Li, Jing; Zhao, Can; Rao, Jia-Sheng [Beihang University, Beijing Key Laboratory for Biomaterials and Neural Regeneration, School of Biological Science and Medical Engineering, Beijing (China); Yang, Fei-Xiang; Yang, Zhao-Yang [Capital Medical University, Department of Neurobiology, School of Basic Medical Sciences, Beijing (China); Wang, Zhan-Jing; Lei, Jian-Feng [Capital Medical University, Medical Experiment and Test Center, Beijing (China); Li, Xiao-Guang [Beihang University, Beijing Key Laboratory for Biomaterials and Neural Regeneration, School of Biological Science and Medical Engineering, Beijing (China); Capital Medical University, Department of Neurobiology, School of Basic Medical Sciences, Beijing (China)

    2017-12-15

    The understanding of microstructural and metabolic changes in the post-traumatic brain injury is the key to brain damage suppression and repair in clinics. Ten female Wistar rats were traumatically injured in the brain CA1 region and above the cortex. Next, diffusion tensor magnetic resonance imaging (DTI) and proton magnetic resonance spectroscopy ({sup 1}H MRS) were used to analyze the microstructural and metabolic changes in the brain within the following 2 weeks. Anisotropy fraction (FA) and axial diffusivity (AD) of the corpus callosum (CC) began to decrease significantly at day 1, whereas radial diffusivity (RD) significantly increased immediately after injury, reflecting the loss of white matter integrity. Compared with day 3, RD decreased significantly at day 7, implicating the angioedema reduction. In the hippocampus, FA significantly increased at day 7; the choline-containing compounds (Cho) and myo-inositol (MI) remarkably increased at day 7 compared with those at day 3, indicating the proliferation of astrocytes and radial glial cells after day 7. No significant differences between DTI and {sup 1}H MRS parameters were observed between day 1 and day 3. Day 1-3 after traumatic brain injury (TBI) may serve as a relatively appropriate time window for treatment planning and the following nerve repair. (orig.)

  9. Alleviating gender role strain in adult men with traumatic brain injury: an evaluation of a set of guidelines for occupational therapy.

    Science.gov (United States)

    Gutman, S A

    1999-01-01

    A set of guidelines to assist men with traumatic brain injury (TBI) to alleviate gender role strain was assessed to determine its effectiveness and acceptability to participants. Four adult male participants with TBI received the intervention (the set of guidelines) for 4 months. The intervention consisted of rebuilding self-identified gendered social roles and activities. Focused interviews and participant observation were used to determine whether gender role strain changed after intervention. The participants reported that the intervention enabled them to (a) enhance their gender role satisfaction through newly rebuilt roles and activities, (b) attain certain long-held personal goals, (c) feel more like members of society, (d) perceive a greater congruency between their internal self-images and external postinjury roles, (e) learn more about personal skills and values as men, (f) feel more comfortable using help-seeking behaviors, (g) feel a sense of shared experience and affinity, (h) feel more understood and accepted, and (i) contribute to others through community member roles. The set of guidelines for alleviating gender role strain was effective in assisting these participants to enhance their gender role satisfaction through rebuilding desired male-gendered social roles and activities. Dating, courtship, extended family member, community member, friend, and mentor-protege roles, lost as a result of TBI, were rebuilt through gender-neutral activities that facilitated a sense of volitional control, competency, and normalcy. Nonetheless, the men continued to lack desired rites of passage leading from male adolescence to adulthood.

  10. The variability of translocator protein signal in brain and blood of genotyped healthy humans using in vivo 123I-CLINDE SPECT imaging

    DEFF Research Database (Denmark)

    Feng, Ling; Jensen, Per; Thomsen, Gerda

    2017-01-01

    123I-CLINDE is a radiotracer developed for SPECT and targets the 18-kDa translocator protein (TSPO). TSPO is upregulated in glial cells and used as a measure of neuroinflammation in a variety of central nervous system diseases. The aim of this study was to examine the test-retest variability of 123...... subjects and a population-based approach in combination with individual whole-blood time-activity curves in the other 8 subjects. Seven brain volumes of interest were extracted and quantified by SUVs and by 2-tissue-compartment modeling for calculation of distribution volumes (VT). Test-retest variability...... was measured by percentage difference (PD), the absolute PD, intraclass correlation coefficient (ICC), and coefficient of variation. Results: The absolute PD of brain SUV and the VT had similar values. The ICC values were higher for VTs than for brain SUVs, which were both moderate to high; however, lower ICC...

  11. Exercise preconditioning reduces brain damage and inhibits TNF-alpha receptor expression after hypoxia/reoxygenation: an in vivo and in vitro study.

    Science.gov (United States)

    Ding, Yun-Hong; Mrizek, Michael; Lai, Qin; Wu, Yimin; Reyes, Raul; Li, Jie; Davis, William W; Ding, Yuchuan

    2006-11-01

    Exercise reduces ischemia and reperfusion injury in rat stroke models. We investigated whether gradual increases in tumor necrosis factor-alpha (TNF-alpha) reported during exercise down-regulates expression of TNF-alpha receptors I and II (TNFRI and II) in stroke, leading to reduced brain damage. Adult male Sprague Dawley rats were subjected to 30 minutes of exercise on a treadmill each day for 3 weeks. Then, stroke was induced by a 2-hour middle cerebral artery (MCA) occlusion using an intra-luminal filament. Expressions of TNFRI and II mRNA in the brain were detected using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Protein expressions of TNFRI and II were determined by enzyme-linked immunoabsorbant assay (ELISA) in serum and brain homogenates. Spatial distribution of TNF-alpha receptors in brain regions was determined with immunocytochemistry. In human umbilical vein endothelial cells (HUVEC), we addressed the causal effect of TNF-alpha pretreatment on TNF I and II expression using ELISA and real-time PCR. In exercised rats after stroke, brain infarct was significantly (p<0.01) reduced in the entire MCA supplied regions, associated with a mild expression of TNFRI and II mRNA and protein. The TNF-alpha receptors were restricted to the ischemic core. In contrast, a robust expression of TNFRI and II molecules was found in non-exercised rats subjected to similar ischemia/reperfusion insults. An in vitro study revealed a causal link between TNF-alpha pretreatment and reduced cellular expression of TNF-alpha receptors under hypoxic/reoxygenated conditions. Our results suggest that reduced-brain damage in ischemic rats after exercise preconditioning may be attributable to the reduced expression of TNF-alpha receptors. Chronically increased TNF-alpha expression was also found to reduce TNFI and II responding to acute ischemia/reperfusion insult.

  12. In vitro and in vivo effects of a novel dimeric inhibitor of PSD-95 on excitotoxicity and functional recovery after experimental traumatic brain injury

    DEFF Research Database (Denmark)

    Sommer, Jens Bak; Bach, Anders; Rytter, Hana Malá

    2017-01-01

    weeks post-trauma, spatial learning and memory were assessed in a water maze, and at 3 months, brains were removed for estimation of lesion volumes. Overall, neither treatment with UCCB01-147 nor MK-801 resulted in significant improvements of cognition and histopathology after CCI. Although MK-801......PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel...

  13. Measurement of creatine kinase reaction rate in human brain using magnetization transfer image-selected in vivo spectroscopy (MT-ISIS) and a volume ³¹P/¹H radiofrequency coil in a clinical 3-T MRI system.

    Science.gov (United States)

    Jeong, Eun-Kee; Sung, Young-Hoon; Kim, Seong-Eun; Zuo, Chun; Shi, Xianfeng; Mellon, Eric A; Renshaw, Perry F

    2011-08-01

    High-energy phosphate metabolism, which allows the synthesis and regeneration of adenosine triphosphate (ATP), is a vital process for neuronal survival and activity. In particular, creatine kinase (CK) serves as an energy reservoir for the rapid buffering of ATP levels. Altered CK enzyme activity, reflecting compromised high-energy phosphate metabolism or mitochondrial dysfunction in the brain, can be assessed using magnetization transfer (MT) MRS. MT (31)P MRS has been used to measure the forward CK reaction rate in animal and human brain, employing a surface radiofrequency coil. However, long acquisition times and excessive radiofrequency irradiation prevent these methods from being used routinely for clinical evaluations. In this article, a new MT (31)P MRS method is presented, which can be practically used to measure the CK forward reaction rate constant in a clinical MRI system employing a volume head (31)P coil for spatial localization, without contamination from the scalp muscle, and an acquisition time of 30 min. Other advantages associated with the method include radiofrequency homogeneity within the regions of interest of the brain using a volume coil with image-selected in vivo spectroscopy localization, and reduction of the specific absorption rate using nonadiabatic radiofrequency pulses for MT saturation. The mean value of k(f) was measured as 0.320 ± 0.075 s(-1) from 10 healthy volunteers with an age range of 18-40 years. These values are consistent with those obtained using earlier methods, and the technique may be used routinely to evaluate energetic processes in the brain on a clinical MRI system. Copyright © 2010 John Wiley & Sons, Ltd.

  14. In vivo and in vitro changes in neurochemical parameters related to mercury concentrations from specific brain regions of polar bears (Ursus maritimus).

    Science.gov (United States)

    Krey, Anke; Kwan, Michael; Chan, Hing Man

    2014-11-01

    Mercury (Hg) has been detected in polar bear brain tissue, but its biological effects are not well known. Relationships between Hg concentrations and neurochemical enzyme activities and receptor binding were assessed in the cerebellum, frontal lobes, and occipital lobes of 24 polar bears collected from Nunavik (Northern Quebec), Canada. The concentration-response relationship was further studied with in vitro experiments using pooled brain homogenate of 12 randomly chosen bears. In environmentally exposed brain samples, there was no correlative relationship between Hg concentration and cholinesterase (ChE) activity or muscarinic acetylcholine receptor (mAChR) binding in any of the 3 brain regions. Monoamine oxidase (MAO) activity in the occipital lobe showed a negative correlative relationship with total Hg concentration. In vitro experiments, however, demonstrated that Hg (mercuric chloride and methylmercury chloride) can inhibit ChE and MAO activities and muscarinic mAChR binding. These results show that Hg can alter neurobiochemical parameters but the current environmental Hg exposure level does have an effect on the neurochemistry of polar bears from northern Canada. © 2014 SETAC.

  15. In vivo measurement of intracellular pH in human brain during different tensions of carbon dioxide in arterial blood. A 31P-NMR study

    DEFF Research Database (Denmark)

    Jensen, K E; Thomsen, C; Henriksen, O

    1988-01-01

    The effect of changes in carbon dioxide tension in arterial blood upon intracellular pH in brain tissue was studied in seven healthy volunteers, aged 22-45 years. The pH changes were monitored by use of 31P nuclear magnetic resonance spectroscopy, performed on a whole-body 1.5 Tesla Siemens imaging...

  16. Conjugates of Superoxide Dismutase 1 with Amphiphilic Poly(2-oxazoline) Block Copolymers for Enhanced Brain Delivery: Synthesis, Characterization and Evaluation in Vitro and in Vivo

    KAUST Repository

    Tong, Jing

    2013-01-07

    Superoxide dismutase 1 (SOD1) efficiently catalyzes dismutation of superoxide, but its poor delivery to the target sites in the body, such as brain, hinders its use as a therapeutic agent for superoxide-associated disorders. Here to enhance the delivery of SOD1 across the blood-brain barrier (BBB) and in neurons the enzyme was conjugated with poly(2-oxazoline) (POx) block copolymers, P(MeOx-b-BuOx) or P(EtOx-b-BuOx), composed of (1) hydrophilic 2-methyl-2-oxazoline (MeOx) or 2-ethyl-2-oxazoline (EtOx) and (2) hydrophobic 2-butyl-2-oxazoline (BuOx) repeating units. The conjugates contained from 2 to 3 POx chains joining the protein amino groups via cleavable -(ss)- or noncleavable -(cc)- linkers at the BuOx block terminus. They retained 30% to 50% of initial SOD1 activity, were conformationally and thermally stable, and assembled in 8 or 20 nm aggregates in aqueous solution. They had little if any toxicity to CATH.a neurons and displayed enhanced uptake in these neurons as compared to native or PEGylated SOD1. Of the two conjugates, SOD1-(cc)-P(MeOx-b-BuOx) and SOD1-(cc)-P(EtOx-b-BuOx), compared, the latter was entering cells 4 to 7 times faster and at 6 h colocalized predominantly with endoplasmic reticulum (41 ± 3%) and mitochondria (21 ± 2%). Colocalization with endocytosis markers and pathway inhibition assays suggested that it was internalized through lipid raft/caveolae, also employed by the P(EtOx-b-BuOx) copolymer. The SOD activity in cell lysates and ability to attenuate angiotensin II (Ang II)-induced superoxide in live cells were increased for this conjugate compared to SOD1 and PEG-SOD1. Studies in mice showed that SOD1-POx had ca. 1.75 times longer half-life in blood than native SOD1 (28.4 vs 15.9 min) and after iv administration penetrated the BBB significantly faster than albumin to accumulate in brain parenchyma. The conjugate maintained high stability both in serum and in brain (77% vs 84% at 1 h postinjection). Its amount taken up by the brain

  17. Cyclopentadienyl tricarbonyl complexes of 99mTc for the in vivo imaging of the serotonin 5-HT 1a receptor in the brain

    International Nuclear Information System (INIS)

    Saidi, Mouldi; Trabelsi, Adel; MEKNI, Abdelkader; Kretzschmar, M.; Sefert, S.; Bergmann, R.; Pietzsch, H.-J.

    2005-01-01

    The present interest in the 5-HT 1a receptor is due to its implicated role in several major neuropsychiatric disorders such as depression, eating disorders and anxiety. For the diagnosis of these pathophysiological processes it is important to have radioligands in hand able to specifically bind on the 5-HT 1a receptor in order to allow brain imaging. due to the optimal radiation properties of 99mTc there is a considerable interest in the development of 99mTc radiopharmaceuticals for imaging serotonergic CNS receptors using single-photon emission tomography (SPET). Here we introduce two cyclopentadienyl technitium tricarbonyl conjugates of piperidine derivatives which show high accumulation of radioactivity in brain areas rich in 5-HT 1a receptors

  18. In vivo labelling of acetyl-aspartyl peptides in mouse brain from intracranially and intracranially and intraperitoneally administered acetyl-L-[U-14C]aspartate

    International Nuclear Information System (INIS)

    Sinichkin, A.; Sterri, S.; Edminson, P.D.; Reichelt, K.L.; Kvamme, E.

    1977-01-01

    Following intracranial and intraperitoneal injection of acetyl-L-[U- 14 C]aspartate into mice about 5% and 0.7% of the radioactivity, respectively, was recovered from the brain after 30 min. On chromatographic separation of the cationic and anionic compounds on a Dowex 50 column, the former fraction contained about 60% of the radioactivity, predominantly as labelled asparate and glutamate. The anionic compounds, containing 20% of the labelled compounds, were fractionated in several chromatographic systems and resolved into a great variety of labelled peptidic compounds of which five acetyl-[U 14 ]aspartyl peptides, containing two to four amino acids, were purified. One of these, acetyl-aspartyl glutamine, has not previously been found in brain. (author)

  19. p-Hydroxy benzoic acid-conjugated dendrimer nanotherapeutics as potential carriers for targeted drug delivery to brain: an in vitro and in vivo evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Swami, Rajan; Singh, Indu [National Institute of Pharmaceutical Education & Research (NIPER), Department of Pharmaceutics (India); Kulhari, Hitesh [CSIR-Indian Institute of Chemical Technology, Medicinal Chemistry & Pharmacology Division (India); Jeengar, Manish Kumar [National Institute of Pharmaceutical Education & Research (NIPER), Departmentof Pharmacology (India); Khan, Wahid, E-mail: wahid@niperhyd.ac.in; Sistla, Ramakrishna, E-mail: sistla@iict.res.in, E-mail: rksistla@yahoo.com [National Institute of Pharmaceutical Education & Research (NIPER), Department of Pharmaceutics (India)

    2015-06-15

    Dendrimers which are discrete nanostructures/nanoparticles are emerging as promising candidates for many nanomedicine applications. Ligand-conjugated dendrimer facilitate the delivery of therapeutics in a targeted manner. Small molecules such as p-hydroxyl benzoic acid (pHBA) were found to have high affinity for sigma receptors which are prominent in most parts of central nervous system and tumors. The aim of this study was to synthesize pHBA-dendrimer conjugates as colloidal carrier for site-specific delivery of practically water insoluble drug, docetaxel (DTX) to brain tumors and to determine its targeting efficiency. pHBA, a small molecule ligand was coupled to the surface amine groups of generation 4-PAMAM dendrimer via a carbodiimide reaction and loaded with DTX. The conjugation was confirmed by {sup 1}HNMR and FT-IR spectroscopy. In vitro release of drug from DTX-loaded pHBA-conjugated dendrimer was found to be less as compared to unconjugated dendrimers. The prepared drug delivery system exhibited good physico-chemical stability and decrease in hemolytic toxicity. Cell viability and cell uptake studies were performed against U87MG human glioblastoma cells and formulations exerted considerable anticancer effect than plain drug. Conjugation of dendrimer with pHBA significantly enhanced the brain uptake of DTX which was shown by the recovery of a higher percentage of the dose from the brain following administration of pHBA-conjugated dendrimers compared with unconjugated dendrimer or formulation in clinical use (Taxotere{sup ®}). Therefore, pHBA conjugated dendrimers could be an efficient delivery vehicle for the targeting of anticancer drugs to brain tumors.

  20. In vivo quantitative whole-brain diffusion tensor imaging analysis of APP/PS1 transgenic mice using voxel-based and atlas-based methods

    International Nuclear Information System (INIS)

    Qin, Yuan-Yuan; Li, Mu-Wei; Oishi, Kenichi; Zhang, Shun; Zhang, Yan; Zhao, Ling-Yun; Zhu, Wen-Zhen; Lei, Hao

    2013-01-01

    Diffusion tensor imaging (DTI) has been applied to characterize the pathological features of Alzheimer's disease (AD) in a mouse model, although little is known about whether these features are structure specific. Voxel-based analysis (VBA) and atlas-based analysis (ABA) are good complementary tools for whole-brain DTI analysis. The purpose of this study was to identify the spatial localization of disease-related pathology in an AD mouse model. VBA and ABA quantification were used for the whole-brain DTI analysis of nine APP/PS1 mice and wild-type (WT) controls. Multiple scalar measurements, including fractional anisotropy (FA), trace, axial diffusivity (DA), and radial diffusivity (DR), were investigated to capture the various types of pathology. The accuracy of the image transformation applied for VBA and ABA was evaluated by comparing manual and atlas-based structure delineation using kappa statistics. Following the MR examination, the brains of the animals were analyzed for microscopy. Extensive anatomical alterations were identified in APP/PS1 mice, in both the gray matter areas (neocortex, hippocampus, caudate putamen, thalamus, hypothalamus, claustrum, amygdala, and piriform cortex) and the white matter areas (corpus callosum/external capsule, cingulum, septum, internal capsule, fimbria, and optic tract), evidenced by an increase in FA or DA, or both, compared to WT mice (p 0.05). The histopathological changes in the gray matter areas were confirmed by microscopy studies. DTI did, however, demonstrate significant changes in white matter areas, where the difference was not apparent by qualitative observation of a single-slice histological specimen. This study demonstrated the structure-specific nature of pathological changes in APP/PS1 mouse, and also showed the feasibility of applying whole-brain analysis methods to the investigation of an AD mouse model. (orig.)

  1. A histology-based atlas of the C57BL/6J mouse brain deformably registered to in vivo MRI for localized radiation and surgical targeting

    International Nuclear Information System (INIS)

    Purger, David; McNutt, Todd; Wong, John; Ford, Eric; Achanta, Pragathi; Quinones-Hinojosa, Alfredo

    2009-01-01

    The C57BL/6J laboratory mouse is commonly used in neurobiological research. Digital atlases of the C57BL/6J brain have been used for visualization, genetic phenotyping and morphometry, but currently lack the ability to accurately calculate deviations between individual mice. We developed a fully three-dimensional digital atlas of the C57BL/6J brain based on the histology atlas of Paxinos and Franklin (2001 The Mouse Brain in Stereotaxic Coordinates 2nd edn (San Diego, CA: Academic)). The atlas uses triangular meshes to represent the various structures. The atlas structures can be overlaid and deformed to individual mouse MR images. For this study, we selected 18 structures from the histological atlas. Average atlases can be created for any group of mice of interest by calculating the mean three-dimensional positions of corresponding individual mesh vertices. As a validation of the atlas' accuracy, we performed deformable registration of the lateral ventricles to 13 MR brain scans of mice in three age groups: 5, 8 and 9 weeks old. Lateral ventricle structures from individual mice were compared to the corresponding average structures and the original histology structures. We found that the average structures created using our method more accurately represent individual anatomy than histology-based atlases alone, with mean vertex deviations of 0.044 mm versus 0.082 mm for the left lateral ventricle and 0.045 mm versus 0.068 mm for the right lateral ventricle. Our atlas representation gives direct spatial deviations for structures of interest. Our results indicate that MR-deformable histology-based atlases represent an accurate method to obtain accurate morphometric measurements of a population of mice, and that this method may be applied to phenotyping experiments in the future as well as precision targeting of surgical procedures or radiation treatment.

  2. A histology-based atlas of the C57BL/6J mouse brain deformably registered to in vivo MRI for localized radiation and surgical targeting

    Science.gov (United States)

    Purger, David; McNutt, Todd; Achanta, Pragathi; Quiñones-Hinojosa, Alfredo; Wong, John; Ford, Eric

    2009-12-01

    The C57BL/6J laboratory mouse is commonly used in neurobiological research. Digital atlases of the C57BL/6J brain have been used for visualization, genetic phenotyping and morphometry, but currently lack the ability to accurately calculate deviations between individual mice. We developed a fully three-dimensional digital atlas of the C57BL/6J brain based on the histology atlas of Paxinos and Franklin (2001 The Mouse Brain in Stereotaxic Coordinates 2nd edn (San Diego, CA: Academic)). The atlas uses triangular meshes to represent the various structures. The atlas structures can be overlaid and deformed to individual mouse MR images. For this study, we selected 18 structures from the histological atlas. Average atlases can be created for any group of mice of interest by calculating the mean three-dimensional positions of corresponding individual mesh vertices. As a validation of the atlas' accuracy, we performed deformable registration of the lateral ventricles to 13 MR brain scans of mice in three age groups: 5, 8 and 9 weeks old. Lateral ventricle structures from individual mice were compared to the corresponding average structures and the original histology structures. We found that the average structures created using our method more accurately represent individual anatomy than histology-based atlases alone, with mean vertex deviations of 0.044 mm versus 0.082 mm for the left lateral ventricle and 0.045 mm versus 0.068 mm for the right lateral ventricle. Our atlas representation gives direct spatial deviations for structures of interest. Our results indicate that MR-deformable histology-based atlases represent an accurate method to obtain accurate morphometric measurements of a population of mice, and that this method may be applied to phenotyping experiments in the future as well as precision targeting of surgical procedures or radiation treatment.

  3. p-Hydroxy benzoic acid-conjugated dendrimer nanotherapeutics as potential carriers for targeted drug delivery to brain: an in vitro and in vivo evaluation

    International Nuclear Information System (INIS)

    Swami, Rajan; Singh, Indu; Kulhari, Hitesh; Jeengar, Manish Kumar; Khan, Wahid; Sistla, Ramakrishna

    2015-01-01

    Dendrimers which are discrete nanostructures/nanoparticles are emerging as promising candidates for many nanomedicine applications. Ligand-conjugated dendrimer facilitate the delivery of therapeutics in a targeted manner. Small molecules such as p-hydroxyl benzoic acid (pHBA) were found to have high affinity for sigma receptors which are prominent in most parts of central nervous system and tumors. The aim of this study was to synthesize pHBA-dendrimer conjugates as colloidal carrier for site-specific delivery of practically water insoluble drug, docetaxel (DTX) to brain tumors and to determine its targeting efficiency. pHBA, a small molecule ligand was coupled to the surface amine groups of generation 4-PAMAM dendrimer via a carbodiimide reaction and loaded with DTX. The conjugation was confirmed by 1 HNMR and FT-IR spectroscopy. In vitro release of drug from DTX-loaded pHBA-conjugated dendrimer was found to be less as compared to unconjugated dendrimers. The prepared drug delivery system exhibited good physico-chemical stability and decrease in hemolytic toxicity. Cell viability and cell uptake studies were performed against U87MG human glioblastoma cells and formulations exerted considerable anticancer effect than plain drug. Conjugation of dendrimer with pHBA significantly enhanced the brain uptake of DTX which was shown by the recovery of a higher percentage of the dose from the brain following administration of pHBA-conjugated dendrimers compared with unconjugated dendrimer or formulation in clinical use (Taxotere ® ). Therefore, pHBA conjugated dendrimers could be an efficient delivery vehicle for the targeting of anticancer drugs to brain tumors

  4. Alleviation of Kainic Acid-Induced Brain Barrier Dysfunction by 4-O-Methylhonokiol in In Vitro and In Vivo Models

    Directory of Open Access Journals (Sweden)

    Jin-Yi Han

    2015-01-01

    Full Text Available This experiment was designed to investigate whether 4-O-methylhonokiol (MH, a principal ingredient of Magnolia (M. officinalis bark, alleviated acute intraperitoneal (i.p. kainic acid- (KA- induced brain blood barrier dysfunction (BBBD via pathological examination and cytological analyses of the brain tissues of mice. KA (10–30 mg/kg time- and dose-dependently increased the water content of brain tissues and induced edema and encephalopathy. However, pretreatment with MH (5 and 20 mg/kg, i.p. significantly reduced the water content of the brain compared to that observed in the KA control group. Furthermore, MH significantly and dose-dependently reversed the remarkable variations in evan’s blue dye (EBD staining and malondialdehyde (MDA levels that were induced by KA (10 mg/kg, i.p.. MH also decreased the elevated seizure scores that were induced by KA (10 mg/kg, i.p. in mice in a manner similar to scavengers such as DMTU and trolox. Additionally, MH significantly scavenged intracellular ROS and Ca2+ within hippocampal cells. The tight junction seals mediated by claudin (Cld-5 were also found to be modulated by MH. MH efficiently reduced 1,1-diphenyl-2-picrylhydrazyl (DPPH (IC50, 52.4 mM and •OH with an electron spin resonance (ESR signal rate constant of 4×109 M-1·S-1, which is close to the reactivity of the vitamin E analog trolox. Taken together, these results suggest that MH may enhance radical scavenging in lipid and hydrophobic environments, which may be important for the physiological activity of the barrier.

  5. p-Hydroxy benzoic acid-conjugated dendrimer nanotherapeutics as potential carriers for targeted drug delivery to brain: an in vitro and in vivo evaluation

    Science.gov (United States)

    Swami, Rajan; Singh, Indu; Kulhari, Hitesh; Jeengar, Manish Kumar; Khan, Wahid; Sistla, Ramakrishna

    2015-06-01

    Dendrimers which are discrete nanostructures/nanoparticles are emerging as promising candidates for many nanomedicine applications. Ligand-conjugated dendrimer facilitate the delivery of therapeutics in a targeted manner. Small molecules such as p-hydroxyl benzoic acid (pHBA) were found to have high affinity for sigma receptors which are prominent in most parts of central nervous system and tumors. The aim of this study was to synthesize pHBA-dendrimer conjugates as colloidal carrier for site-specific delivery of practically water insoluble drug, docetaxel (DTX) to brain tumors and to determine its targeting efficiency. pHBA, a small molecule ligand was coupled to the surface amine groups of generation 4-PAMAM dendrimer via a carbodiimide reaction and loaded with DTX. The conjugation was confirmed by 1HNMR and FT-IR spectroscopy. In vitro release of drug from DTX-loaded pHBA-conjugated dendrimer was found to be less as compared to unconjugated dendrimers. The prepared drug delivery system exhibited good physico-chemical stability and decrease in hemolytic toxicity. Cell viability and cell uptake studies were performed against U87MG human glioblastoma cells and formulations exerted considerable anticancer effect than plain drug. Conjugation of dendrimer with pHBA significantly enhanced the brain uptake of DTX which was shown by the recovery of a higher percentage of the dose from the brain following administration of pHBA-conjugated dendrimers compared with unconjugated dendrimer or formulation in clinical use (Taxotere®). Therefore, pHBA conjugated dendrimers could be an efficient delivery vehicle for the targeting of anticancer drugs to brain tumors.

  6. Identification and Quantitation of Phenylalanine in the Brain of Patients with Phenylketonuria by Means of Localized in Vivo1H Magnetic-Resonance Spectroscopy

    Science.gov (United States)

    Kreis, R.; Pietz, J.; Penzien, J.; Herschkowitz, N.; Boesch, C.

    Localized proton MR spectroscopy was used to identify phenylalanine (PHE) and to quantitate its cerebral concentration in patients with type I phenylketonuria (PKU). Data acquisition was optimized for the detection of low-concentration metabolites, using a short TE (20 ms) double Hahn-echo localization sequence for large volumes within the head coil and for smaller volumes using a surface coil, Previously described methods to quantitate localized MR spectra were extended to cover the case of low-concentration metabolites, unevenly distributed in three brain compartments and measured in difference spectra only. PHE content was determined in difference spectra of four PKU patients with respect to normals and in one patient before and after an oral load of L-PHE, PHE concentrations of 0.3 to 0.6 mmol/kg brain tissue were obtained, resulting in a concentration gradient for PHE between blood and brain tissue of 2.4 to 3.0, No significant changes were found for the abundant metabolites in gray or white matter. Previously reported MRI changes were confirmed to be due to increased cerebro-spinal-fluid-like spaces.

  7. Evaluation of dopamine transporters and D2 receptors in hemiparkinsonian rat brains in vivo using consecutive PET scans of [18F]FPCIT and [18F]fallypride

    International Nuclear Information System (INIS)

    Choi, Jae Yong; Kim, Chul Hoon; Jeon, Tae Joo; Cho, Won Gil; Lee, Jin Suk; Lee, Soo Jin; Choi, Tae Hyun; Kim, Byoung Soo; Yi, Chi Hoon; Seo, Youngbeom; Yi, Dae Ik; Han, Sang Jin; Lee, Minkyung; Kim, Dong Goo; Lee, Jong Doo; An, Gwangil

    2012-01-01

    The aim of this study was to investigate dopaminergic function in unilaterally lesioned 6-OHDA rats by dual PET radioligands: [ 18 F]FPCIT (a dopamine transporter imaging radioligand) and [ 18 F]fallypride (a dopamine D2 receptors imaging radioligand). As a result, the brain uptake of [ 18 F]FPCIT was significantly reduced and that of [ 18 F]fallypride was increased in the ipsilateral striatum (lesion side) of the 6-OHDA rats. These findings implicated that dopamine transporter is down-regulated and dopamine D2 receptor is up-regulated in this hemiparkinsonian rat model. - Highlights: ► The dopaminergic integrity in unilateral 6-OHDA was evaluated by dual PET tracers. ► The brain uptake and BP ND of [ 18 F]FPCIT was greatly decreased. ► The brain uptake and BP ND [ 18 F]fallypride was slightly increased. ► DAT are down-regulated and D2R are up-regulated.

  8. Design, construction, and in vivo feasibility of a positioning device for irradiation of mice brains using a clinical linear accelerator and intensity modulated radiation therapy.

    Science.gov (United States)

    Rancilio, Nicholas J; Dahl, Shaun; Athanasiadi, Ilektra; Perez-Torres, Carlos J

    2017-12-01

    The goal of this study was to design a positioning device that would allow for selective irradiation of the mouse brain with a clinical linear accelerator. We designed and fabricated an immobilization fixture that incorporates three functions: head stabilizer (through ear bars and tooth bar), gaseous anesthesia delivery and scavenging, and tissue mimic/bolus. Cohorts of five mice were irradiated such that each mouse in the cohort received a unique dose between 1000 and 3000 cGy. DNA damage immunohistochemistry was used to validate an increase in biological effect as a function of radiation dose. Mice were then followed with hematoxylin and eosin (H&E) and anatomical magnetic resonance imaging (MRI). There was evidence of DNA damage throughout the brain proportional to radiation dose. Radiation-induced damage at the prescribed doses, as depicted by H&E, appeared to be constrained to the white matter consistent with radiological observation in human patients. The severity of the damage correlated with the radiation dose as expected. We have designed and manufactured a device that allows us to selectively irradiate the mouse brain with a clinical linear accelerator. However, some off-target effects are possible with large prescription doses.

  9. Simultaneous measurement of neuronal and glial metabolism in rat brain in vivo using co-infusion of [1,6- 13C 2]glucose and [1,2- 13C 2]acetate

    Science.gov (United States)

    Deelchand, Dinesh K.; Nelson, Christopher; Shestov, Alexander A.; Uğurbil, Kâmil; Henry, Pierre-Gilles

    2009-02-01

    In this work the feasibility of measuring neuronal-glial metabolism in rat brain in vivo using co-infusion of [1,6- 13C 2]glucose and [1,2- 13C 2]acetate was investigated. Time courses of 13C spectra were measured in vivo while infusing both 13C-labeled substrates simultaneously. Individual 13C isotopomers (singlets and multiplets observed in 13C spectra) were quantified automatically using LCModel. The distinct 13C spectral pattern observed in glutamate and glutamine directly reflected the fact that glucose was metabolized primarily in the neuronal compartment and acetate in the glial compartment. Time courses of concentration of singly and multiply-labeled isotopomers of glutamate and glutamine were obtained with a temporal resolution of 11 min. Although dynamic metabolic modeling of these 13C isotopomer data will require further work and is not reported here, we expect that these new data will allow more precise determination of metabolic rates as is currently possible when using either glucose or acetate as the sole 13C-labeled substrate.

  10. Evaluation of [18F]-ATRi as PET tracer for in vivo imaging of ATR in mouse models of brain cancer

    International Nuclear Information System (INIS)

    Carlucci, Giuseppe; Carney, Brandon; Sadique, Ahmad; Vansteene, Axel; Tang, Jun; Reiner, Thomas

    2017-01-01

    Rationale: Ataxia telangiectasia and Rad3-related (ATR) threonine serine kinase is one of the key elements in orchestrating the DNA damage response (DDR). As such, inhibition of ATR can amplify the effects of chemo- and radiation-therapy, and several ATR inhibitors (ATRi) have already undergone clinical testing in cancer. For more accurate patient selection, monitoring and staging, real-time in vivo imaging of ATR could be invaluable; the development of appropriate imaging agents has remained a major challenge. Methods: 3-amino-N-(4-[ 18 F]phenyl)-6-(4-(methylsulfonyl)phenyl) pyrazine-2-carboxamide ([ 18 F]-ATRi), a close analogue of Ve-821, (a clinical ATRi candidate), was readily accomplished similarly to already established synthetic procedures. Structurally, 18 F was introduced at the 4-position of the aromatic ring of Ve-821 for generating a labeled ATR inhibitor. In vitro experiments were conducted in U251 MG glioblastoma cell lines and ex vivo biodistribution were perfor