uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Nilsson, Anna
Publications (10 of 34) Show all publications
Shariatgorji, M., Nilsson, A., Fridjonsdottir, E., Vallianatou, T., Källbäck, P., Katan, L., . . . Andrén, P. E. (2019). Comprehensive mapping of neurotransmitter networks by MALDI-MS imaging. Nature Methods, 16(10), 1021-1028
Open this publication in new window or tab >>Comprehensive mapping of neurotransmitter networks by MALDI-MS imaging
Show others...
2019 (English)In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 16, no 10, p. 1021-1028Article in journal (Refereed) Published
Abstract [en]

We present a mass spectrometry imaging (MSI) approach for the comprehensive mapping of neurotransmitter networks in specific brain regions. Our fluoromethylpyridinium-based reactive matrices facilitate the covalent charge-tagging of molecules containing phenolic hydroxyl and/or primary or secondary amine groups, including dopaminergic and serotonergic neurotransmitters and their associated metabolites. These matrices improved the matrix-assisted laser desorption/ionization (MALDI)-MSI detection limit toward low-abundance neurotransmitters and facilitated the simultaneous imaging of neurotransmitters in fine structures of the brain at a lateral resolution of 10 mu m. We demonstrate strategies for the identification of unknown molecular species using the innate chemoselectivity of the reactive matrices and the unique isotopic pattern of a brominated reactive matrix. We illustrate the capabilities of the developed method on Parkinsonian brain samples from human post-mortem tissue and animal models. The direct imaging of neurotransmitter systems provides a method for exploring how various neurological diseases affect specific brain regions through neurotransmitter modulation.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-395725 (URN)10.1038/s41592-019-0551-3 (DOI)000488225900033 ()31548706 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RIF14-0078EU, FP7, Seventh Framework Programme, 607517Swedish Research Council, 2018-03320Swedish Research Council, 2018-05501Swedish Research Council, 2018-05133
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Vallianatou, T., Shariatgorji, M., Nilsson, A., Fridjonsdottir, E., Källback, P., Schintu, N., . . . Andrén, P. E. (2019). Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition. Neuropsychopharmacology, 44, 2091-2098
Open this publication in new window or tab >>Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition
Show others...
2019 (English)In: Neuropsychopharmacology, ISSN 0893-133X, Vol. 44, p. 2091-2098Article in journal (Refereed) Published
Abstract [en]

The neurotransmitter of the cholinergic system, acetylcholine plays a major role in the brain's cognitive function and is involved in neurodegenerative disorders. Here, we present age-related alterations of acetylcholine levels after administration of the acetylcholinesterase inhibitor drug tacrine in normal mice. Using a quantitative, robust and molecular-specific mass spectrometry imaging method we found that tacrine administration significantly raised acetylcholine levels in most areas of sectioned mice brains, inter alia the striatum, hippocampus and cortical areas. However, acetylcholine levels in retrosplenial cortex were significantly lower in 14-month-old than in 12-week-old animals following its administration, indicating that normal aging affects the cholinergic system's responsivity. This small brain region is interconnected with an array of brain networks and is involved in numerous cognitive tasks. Simultaneous visualization of distributions of tacrine and its hydroxylated metabolites in the brain revealed a significant decrease in levels of the metabolites in the 14-month-old mice. The results highlight strengths of the imaging technique to simultaneously investigate multiple molecular species and the drug-target effects in specific regions of the brain. The proposed approach has high potential in studies of neuropathological conditions and responses to neuroactive treatments.

Keywords
mass spectrometry imaging, acetylcholine, retrosplenial cortex, tacrine, aging
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-392312 (URN)10.1038/s41386-019-0397-5 (DOI)000490174900013 ()31009936 (PubMedID)
Funder
Swedish Research Council, 2018-03320Swedish Research Council, 2018-05501EU, FP7, Seventh Framework Programme, 607517The Swedish Brain FoundationSwedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-11-08Bibliographically approved
Vallianatou, T., Strittmatter, N., Nilsson, A., Shariatgorji, M., Hamm, G., Pereira, M., . . . Andrén, P. E. (2018). A mass spectrometry imaging approach for investigating how drug-drug interactions influence drug blood-brain barrier permeability. NeuroImage, 172, 808-816
Open this publication in new window or tab >>A mass spectrometry imaging approach for investigating how drug-drug interactions influence drug blood-brain barrier permeability
Show others...
2018 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 172, p. 808-816Article in journal (Refereed) Published
Abstract [en]

There is a high need to develop quantitative imaging methods capable of providing detailed brain localization information of several molecular species simultaneously. In addition, extensive information on the effect of the blood-brain barrier on the penetration, distribution and efficacy of neuroactive compounds is required. Thus, we have developed a mass spectrometry imaging method to visualize and quantify the brain distribution of drugs with varying blood-brain barrier permeability. With this approach, we were able to determine blood-brain barrier transport of different drugs and define the drug distribution in very small brain structures (e.g., choroid plexus) due to the high spatial resolution provided. Simultaneously, we investigated the effect of drug-drug interactions by inhibiting the membrane transporter multidrug resistance 1 protein. We propose that the described approach can serve as a valuable analytical tool during the development of neuroactive drugs, as it can provide physiologically relevant information often neglected by traditional imaging technologies.

Keywords
Mass spectrometry imaging, Blood-brain barrier, Drug-drug interactions, Elacridar, Loperamide, Propranolol
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-353358 (URN)10.1016/j.neuroimage.2018.01.013 (DOI)000430364100067 ()29329980 (PubMedID)
Funder
Swedish Research Council, 2013-3105]Swedish Research Council, 2014-6215]Swedish Foundation for Strategic Research , RIF14-0078]AstraZenecaEU, FP7, Seventh Framework Programme, 607517The Swedish Brain FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-06-12 Created: 2018-06-12 Last updated: 2019-09-02Bibliographically approved
Källback, P., Nilsson, A. & Andrén, P. E. (2018). A Space Efficient Direct Access Data Compression Approach for Mass Spectrometry Imaging. Analytical Chemistry, 90(6), 3676-3682
Open this publication in new window or tab >>A Space Efficient Direct Access Data Compression Approach for Mass Spectrometry Imaging
2018 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 6, p. 3676-3682Article in journal (Refereed) Published
Abstract [en]

Advances in mass spectrometry imaging that improve both spatial and mass resolution are resulting in increasingly larger data files that are difficult to handle with current software. We have developed a novel near-lossless compression method with data entropy reduction that reduces the file size significantly. The reduction in data size can be set at four different levels (coarse, medium, fine, and superfine) prior to running the data compression. This can be applied to spectra or spectrum-by-spectrum, or it can be applied to transpose arrays or array-by-array, to efficiently read the data without decompressing the whole data set. The results show that a compression ratio of up to 5.9:1 was achieved for data from commercial mass spectrometry software programs and 55:1 for data from our in-house developed mslQuant program. Comparing the average signals from regions of interest, the maximum deviation was 0.2% between compressed and uncompressed data sets with coarse accuracy for the data entropy reduction. In addition, when accessing the compressed data by selecting a random m/z value using mslQuant, the time to update an image on the computer screen was only slightly increased from 92 (+/- 32) ms (uncompressed) to 114 (+/- 13) ms (compressed). Furthermore, the compressed data can be stored on readily accessible servers for data evaluation without further data reprocessing. We have developed a space efficient, direct access data compression algorithm for mass spectrometry imaging, which can be used for various data-demanding mass spectrometry imaging applications.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Pharmaceutical Sciences Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-328051 (URN)10.1021/acs.analchem.7b03188 (DOI)000428219600007 ()
Funder
Swedish Research Council, 521-2013-3105 621-2014-6215The Swedish Brain FoundationSwedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-08-19 Created: 2017-08-19 Last updated: 2018-06-28Bibliographically approved
Swales, J. G., Dexter, A., Hamm, G., Nilsson, A., Strittmatter, N., Michopoulos, F., . . . Goodwin, R. J. A. (2018). Quantitation of Endogenous Metabolites in Mouse Tumors Using Mass-Spectrometry Imaging. Analytical Chemistry, 90(10), 6051-6058
Open this publication in new window or tab >>Quantitation of Endogenous Metabolites in Mouse Tumors Using Mass-Spectrometry Imaging
Show others...
2018 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 10, p. 6051-6058Article in journal (Refereed) Published
Abstract [en]

Described is a quantitative-mass-spectrometry-imaging (qMSI) methodology for the analysis of lactate and glutamate distributions in order to delineate heterogeneity among mouse tumor models used to support drug-discovery efficacy testing. We evaluate and report on preanalysis-stabilization methods aimed at improving the reproducibility and efficiency of quantitative assessments of endogenous molecules in tissues. Stability experiments demonstrate that optimum stabilization protocols consist of frozen-tissue embedding, post-tissue-sectioning desiccation, and storage at -80 degrees C of tissue sections sealed in vacuum-tight containers. Optimized stabilization protocols are used in combination with qMSI methodology for the absolute quantitation of lactate and glutamate in tumors, incorporating the use of two different stable-isotope-labeled versions of each analyte and spectral-clustering performed on each tissue section using k-means clustering to allow region-specific, pixel-by-pixel quantitation. Region-specific qMSI was used to screen different tumor models and identify a phenotype that has low lactate heterogeneity, which will enable accurate measurements of lactate modulation in future drug-discovery studies. We conclude that using optimized qMSI protocols, it is possible to quantify endogenous metabolites within tumors, and region-specific quantitation can provide valuable insight into tissue heterogeneity and the tumor microenvironment.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-356451 (URN)10.1021/acs.analchem.7b05239 (DOI)000432478600013 ()29668267 (PubMedID)
Funder
Swedish Research Council, 2014-6215Swedish Foundation for Strategic Research , RIF14-0078AstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-08-01 Created: 2018-08-01 Last updated: 2018-08-01Bibliographically approved
Zhang, X., Mantas, I., Alvarsson, A., Yoshitake, T., Shariatgorji, M., Pereira, M., . . . Svenningsson, P. (2018). Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or beta-Phenylethylamine. Frontiers in Pharmacology, 9, Article ID 166.
Open this publication in new window or tab >>Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or beta-Phenylethylamine
Show others...
2018 (English)In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 166Article in journal (Refereed) Published
Abstract [en]

The trace amine-associated receptor 1 (TAAR1) is expressed by dopaminergic neurons, but the precise influence of trace amines upon their functional activity remains to be fully characterized. Here, we examined the regulation of tyrosine hydroxylase (TH) by tyramine and beta-phenylethylamine (beta-PEA) compared to 3-iodothyronamine (T(1)AM). Immunoblotting and amperometry were performed in dorsal striatal slices from wildtype (WT) and TAAR1 knockout (KO) mice. T(1)AM increased TH phosphorylation at both Ser(19) and Ser(40), actions that should promote functional activity of TH. Indeed, HPLC data revealed higher rates of L-dihydroxyphenylalanine (DOPA) accumulation in WT animals treated with T(1)AM after the administration of a DOPA decarboxylase inhibitor. These effects were abolished both in TAAR1 KO mice and by the TAAR1 antagonist, EPPTB. Further, they were specific inasmuch as Ser(845) phosphorylation of the post-synaptic GluA1 AMPAR subunit was unaffected. The effects of T1AM on TH phosphorylation at both Ser(19) (CamKII-targeted), and Ser40 (PKA-phosphorylated) were inhibited by KN-92 and H-89, inhibitors of CamKII and PKA respectively. Conversely, there was no effect of an EPAC analog, 8-CPT-2Me-cAMP, on TH phosphorylation. In line with these data, T(1)AM increased evoked striatal dopamine release in TAAR1 WT mice, an action blunted in TAAR1 KO mice and by EPPTB. Mass spectrometry imaging revealed no endogenous T(1)AM in the brain, but detected T(1)AM in several brain areas upon systemic administration in both WT and TAAR1 KO mice. In contrast to T1AM, tyramine decreased the phosphorylation of Ser40-TH, while increasing Ser(845)-GluA1 phosphorylation, actions that were not blocked in TAAR1 KO mice. Likewise, beta-PEA reduced Ser(40)-TH and tended to promote Ser845-GluA1 phosphorylation. The D-1 receptor antagonist SCH23390 blocked tyramine-induced Ser(845)-GluA1 phosphorylation, but had no effect on tyramine-or beta-PEA-induced Ser(40)-TH phosphorylation. In conclusion, by intracellular cascades involving CaMKII and PKA, T(1)AM, but not tyramine and beta-PEA, acts via TAAR1 to promote the phosphorylation and functional activity of TH in the dorsal striatum, supporting a modulatory influence on dopamine transmission.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
trace amine-associated receptor 1, tyrosine hydroxylase, evoked dopamine release, tyramine, T(1)AM
National Category
Pharmacology and Toxicology Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-350493 (URN)10.3389/fphar.2018.00166 (DOI)000426374600001 ()
Funder
Swedish Research CouncilSwedish Research Council, 2013-3105Swedish Research Council, 2014-6215]Swedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-05-09 Created: 2018-05-09 Last updated: 2018-05-09Bibliographically approved
Bäckström, E., Hamm, G., Nilsson, A., Fihn, B.-M., Strittmatter, N., Andrén, P., . . . Fridén, M. (2018). Uncovering the regional localization of inhaled salmeterol retention in the lung. Drug Delivery, 25(1), 838-845
Open this publication in new window or tab >>Uncovering the regional localization of inhaled salmeterol retention in the lung
Show others...
2018 (English)In: Drug Delivery, ISSN 1071-7544, E-ISSN 1521-0464, Vol. 25, no 1, p. 838-845Article in journal (Refereed) Published
Abstract [en]

Treatment of respiratory disease with a drug delivered via inhalation is generally held as being beneficial as it provides direct access to the lung target site with a minimum systemic exposure. There is however only limited information of the regional localization of drug retention following inhalation. The aim of this study was to investigate the regional and histological localization of salmeterol retention in the lungs after inhalation and to compare it to systemic administration. Lung distribution of salmeterol delivered to rats via nebulization or intravenous (IV) injection was analyzed with high-resolution mass spectrometry imaging (MSI). Salmeterol was widely distributed in the entire section at 5 min after inhalation, by 15 min it was preferentially retained in bronchial tissue. Via a novel dual-isotope study, where salmeterol was delivered via inhalation and d(3)-salmeterol via IV to the same rat, could the effective gain in drug concentration associated with inhaled delivery relative to IV, expressed as a site-specific lung targeting factor, was 5-, 31-, and 45-fold for the alveolar region, bronchial sub-epithelium and epithelium, respectively. We anticipate that this MSI-based framework for quantifying regional and histological lung targeting by inhalation will accelerate discovery and development of local and more precise treatments of respiratory disease.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2018
Keywords
Pulmonary distribution, lung retention, mass spectrometry imaging, pharmacokinetics, inhalation
National Category
Respiratory Medicine and Allergy Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-354345 (URN)10.1080/10717544.2018.1455762 (DOI)000428782700002 ()29587546 (PubMedID)
Funder
AstraZenecaSwedish Research Council, 2014-6215Swedish Foundation for Strategic Research , RIF14-0078
Available from: 2018-08-07 Created: 2018-08-07 Last updated: 2018-08-07Bibliographically approved
Hulme, H. E., Meikle, L. M., Wessel, H., Strittmatter, N., Swales, J., Thomson, C., . . . Wall, D. M. (2017). Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection. Scientific Reports, 7, Article ID 2786.
Open this publication in new window or tab >>Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection
Show others...
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 2786Article in journal (Refereed) Published
Abstract [en]

Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S. Typhimurium infection. To further understand host-pathogen interactions at this site, we used mass spectrometry imaging (MSI) to analyse MLN tissue from a murine model of S. Typhimurium infection. A molecule, identified as palmitoylcarnitine (PalC), was of particular interest due to its high abundance at loci of S. Typhimurium infection and MLN disruption. High levels of PalC localised to sites within the MLNs where B and T cells were absent and where the perimeter of CD169(+) sub capsular sinus macrophages was disrupted. MLN cells cultured ex vivo and treated with PalC had reduced CD4(+) CD25(+) T cells and an increased number of B220(+) CD19(+) B cells. The reduction in CD4(+) CD25(+) T cells was likely due to apoptosis driven by increased caspase-3/7 activity. These data indicate that PalC significantly alters the host response in the MLNs, acting as a decisive factor in infection outcome.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
National Category
Infectious Medicine Pharmaceutical Biotechnology
Identifiers
urn:nbn:se:uu:diva-327224 (URN)10.1038/s41598-017-03100-5 (DOI)000402690200002 ()28584281 (PubMedID)
Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2017-08-16Bibliographically approved
Nilsson, A., Peric, A., Strimfors, M., Goodwin, R. J. A., Hayes, M. A., Andrén, P. E. & Hilgendorf, C. (2017). Mass Spectrometry Imaging proves differential absorption profiles of well-characterised permeability markers along the crypt-villus axis. Scientific Reports, 7, Article ID 6352.
Open this publication in new window or tab >>Mass Spectrometry Imaging proves differential absorption profiles of well-characterised permeability markers along the crypt-villus axis
Show others...
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6352Article in journal (Refereed) Published
Abstract [en]

Knowledge about the region-specific absorption profiles from the gastrointestinal tract of orally administered drugs is a critical factor guiding dosage form selection in drug development. We have used a novel approach to study three well-characterized permeability and absorption marker drugs in the intestine. Propranolol and metoprolol (highly permeable compounds) and atenolol (low-moderate permeability compound) were orally co-administered to rats. The site of drug absorption was revealed by high spatial resolution matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and complemented by quantitative measurement of drug concentration in tissue homogenates. MALDI-MSI identified endogenous molecular markers that illustrated the villi structures and confirmed the different absorption sites assigned to histological landmarks for the three drugs. Propranolol and metoprolol showed a rapid absorption and shorter transit distance in contrast to atenolol, which was absorbed more slowly from more distal sites. This study provides novel insights into site specific absorption for each of the compounds along the crypt-villus axis, as well as confirming a proximal-distal absorption gradient along the intestine. The combined analytical approach allowed the quantification and spatial resolution of drug distribution in the intestine and provided experimental evidence for the suggested absorption behaviour of low and highly permeable compounds.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical Engineering
Identifiers
urn:nbn:se:uu:diva-332846 (URN)10.1038/s41598-017-06583-4 (DOI)000406273700004 ()28743866 (PubMedID)
Funder
Swedish Research Council, 2014-6215Swedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience, 452300027AstraZeneca
Available from: 2017-11-08 Created: 2017-11-08 Last updated: 2017-11-08Bibliographically approved
Ashton, S., Song, Y. H., Nolan, J., Cadogan, E., Murray, J., Odedra, R., . . . Barry, S. T. (2016). Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo. Science Translational Medicine, 8(325), Article ID 325ra17.
Open this publication in new window or tab >>Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo
Show others...
2016 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 325, article id 325ra17Article in journal (Refereed) Published
Abstract [en]

Efforts to apply nanotechnology in cancer have focused almost exclusively on the delivery of cytotoxic drugs to improve therapeutic index. There has been little consideration of molecularly targeted agents, in particular kinase inhibitors, which can also present considerable therapeutic index limitations. We describe the development of Accurin polymeric nanoparticles that encapsulate the clinical candidate AZD2811, an Aurora B kinase inhibitor, using an ion pairing approach. Accurins increase biodistribution to tumor sites and provide extended release of encapsulated drug payloads. AZD2811 nanoparticles containing pharmaceutically acceptable organic acids as ion pairing agents displayed continuous drug release for more than 1 week in vitro and a corresponding extended pharmacodynamic reduction of tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration. A specific AZD2811 nanoparticle formulation profile showed accumulation and retention in tumors with minimal impact on bone marrow pathology, and resulted in lower toxicity and increased efficacy in multiple tumor models at half the dose intensity of AZD1152, a water-soluble prodrug of AZD2811. These studies demonstrate that AZD2811 can be formulated in nanoparticles using ion pairing agents to give improved efficacy and tolerability in preclinical models with less frequent dosing. Accurins specifically, and nanotechnology in general, can increase the therapeutic index of molecularly targeted agents, including kinase inhibitors targeting cell cycle and oncogenic signal transduction pathways, which have to date proved toxic in humans.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-279559 (URN)10.1126/scitranslmed.aad2355 (DOI)000369694300003 ()26865565 (PubMedID)
Funder
AstraZeneca
Available from: 2016-03-02 Created: 2016-03-02 Last updated: 2018-01-10Bibliographically approved
Organisations

Search in DiVA

Show all publications