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  • 1.
    Andrén, Per E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Goodwin, Richard
    AstraZeneca, Drug Safety & Metab, Cambridge, England..
    Investigating drug-induced toxicity in tissue samples using mass spectrometry imaging2016In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, no S, p. S42-S42Article in journal (Other academic)
  • 2.
    Ashton, Susan
    et al.
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Song, Young Ho
    BIND Therapeut, 325 Vassar St, Cambridge, MA 02139 USA..
    Nolan, Jim
    BIND Therapeut, 325 Vassar St, Cambridge, MA 02139 USA..
    Cadogan, Elaine
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Murray, Jim
    AstraZeneca, Pharmaceut Dev, Macclesfield SK10 2NX, Cheshire, England..
    Odedra, Rajesh
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Foster, John
    AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England..
    Hall, Peter A.
    AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England..
    Low, Susan
    BIND Therapeut, 325 Vassar St, Cambridge, MA 02139 USA..
    Taylor, Paula
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Ellston, Rebecca
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Polanska, Urszula M.
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Wilson, Joanne
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Howes, Colin
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Smith, Aaron
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Goodwin, Richard J. A.
    AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England..
    Swales, John G.
    AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England..
    Strittmatter, Nicole
    Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London SW7 2AZ, England..
    Takats, Zoltan
    Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London SW7 2AZ, England..
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andrén, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Trueman, Dawn
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Walker, Mike
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Reimer, Corinne L.
    AstraZeneca, Oncol iMED, Gatehouse Pk, Boston, MA 02451 USA..
    Troiano, Greg
    BIND Therapeut, 325 Vassar St, Cambridge, MA 02139 USA..
    Parsons, Donald
    BIND Therapeut, 325 Vassar St, Cambridge, MA 02139 USA..
    De Witt, David
    BIND Therapeut, 325 Vassar St, Cambridge, MA 02139 USA..
    Ashford, Marianne
    AstraZeneca, Pharmaceut Dev, Macclesfield SK10 2NX, Cheshire, England..
    Hrkach, Jeff
    BIND Therapeut, 325 Vassar St, Cambridge, MA 02139 USA..
    Zale, Stephen
    BIND Therapeut, 325 Vassar St, Cambridge, MA 02139 USA..
    Jewsbury, Philip J.
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Barry, Simon T.
    AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
    Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo2016In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 325, article id 325ra17Article in journal (Refereed)
    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.

  • 3. Bourdenx, Mathieu
    et al.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wadensten, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fälth, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Li, Qin
    Crossman, Alan R.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bezard, Erwan
    Abnormal structure-specific peptide transmission and processing in a primate model of Parkinson's disease and L-DOPA-induced dyskinesia2014In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 62, p. 307-312Article in journal (Refereed)
    Abstract [en]

    A role for enhanced peptidergic transmission, either opioidergic or not, has been proposed for the generation of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) on the basis of in situ hybridization studies showing that striatal peptidergic precursor expression consistently correlates with LID severity. Few studies, however, have focused on the actual peptides derived from these precursors. We used mass-spectrometry to study peptide profiles in the putamen and globus pallidus (internalis and externalis) collected from 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine treated macaque monkeys, acutely or chronically treated with L-DOPA. We identified that parkinsonian and dyskinetic states are associated with an abnormal production of proenkephalin-, prodynorphin- and protachykinin-1-derived peptides in both segments of the globus pallidus. Moreover, we report that peptidergic processing is dopamine-state dependent and highly structure-specific, possibly explaining the failure of previous clinical trials attempting to rectify abnormal peptidergic transmission.

  • 4.
    Bäckström, Erica
    et al.
    AstraZeneca, Resp Inflammat & Autoimmun IMED Biotech Unit, Drug Metab & Pharmacokinet, Gothenburg, Sweden.
    Hamm, Gregory
    AstraZeneca, Pathol Sci Drug Safety & Metab IMED Biotech Unit, Cambridge, England.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fihn, Britt-Marie
    AstraZeneca, Resp Inflammat & Autoimmun IMED Biotech Unit, Drug Metab & Pharmacokinet, Gothenburg, Sweden.
    Strittmatter, Nicole
    AstraZeneca, Pathol Sci Drug Safety & Metab IMED Biotech Unit, Cambridge, England.
    Andrén, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Goodwin, Richard J. A.
    AstraZeneca, Pathol Sci Drug Safety & Metab IMED Biotech Unit, Cambridge, England.
    Fridén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca, Resp Inflammat & Autoimmun IMED Biotech Unit, Drug Metab & Pharmacokinet, Gothenburg, Sweden.
    Uncovering the regional localization of inhaled salmeterol retention in the lung2018In: Drug Delivery, ISSN 1071-7544, E-ISSN 1521-0464, Vol. 25, no 1, p. 838-845Article in journal (Refereed)
    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.

  • 5. Cobice, D. F.
    et al.
    Goodwin, R. J. A.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mackay, C. L.
    Andrew, R.
    Future technology insight: mass spectrometry imaging as a tool in drug research and development2015In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 172, no 13, p. 3266-3283Article, review/survey (Refereed)
    Abstract [en]

    In pharmaceutical research, understanding the biodistribution, accumulation and metabolism of drugs in tissue plays a key role during drug discovery and development. In particular, information regarding pharmacokinetics, pharmacodynamics and transport properties of compounds in tissues is crucial during early screening. Historically, the abundance and distribution of drugs have been assessed by well-established techniques such as quantitative whole-body autoradiography (WBA) or tissue homogenization with LC/MS analysis. However, WBA does not distinguish active drug from its metabolites and LC/MS, while highly sensitive, does not report spatial distribution. Mass spectrometry imaging (MSI) can discriminate drug and its metabolites and endogenous compounds, while simultaneously reporting their distribution. MSI data are influencing drug development and currently used in investigational studies in areas such as compound toxicity. In in vivo studies MSI results may soon be used to support new drug regulatory applications, although clinical trial MSI data will take longer to be validated for incorporation into submissions. We review the current and future applications of MSI, focussing on applications for drug discovery and development, with examples to highlight the impact of this promising technique in early drug screening. Recent sample preparation and analysis methods that enable effective MSI, including quantitative analysis of drugs from tissue sections will be summarized and key aspects of methodological protocols to increase the effectiveness of MSI analysis for previously undetectable targets addressed. These examples highlight how MSI has become a powerful tool in drug research and development and offers great potential in streamlining the drug discovery process.

  • 6. Fridjonsdottir, Elva
    et al.
    Vallianatou, Theodosia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svenningsson, Per
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Imaging aging effects on the catecholamine, serotonin, and histamine neurotransmitter systems in specific brain regionsManuscript (preprint) (Other academic)
  • 7.
    Goodwin, Richard J A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mackay, C Logan
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Harrison, David J
    Farde, Lars
    Karolinska Institutet.
    Andrén, Per E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Iverson, Suzanne L
    Qualitative and Quantitative MALDI Imaging of the Positron Emission Tomography Ligands Raclopride (a D2 Dopamine Antagonist) and SCH 23390 (a D1 Dopamine Antagonist) in Rat Brain Tissue Sections Using a Solvent-Free Dry Matrix Application Method2011In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 83, no 24, p. 9694-9701Article in journal (Refereed)
    Abstract [en]

    The distributions of positron emission tomography (PET) ligands in rat brain tissue sections were analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). The detection of the PET ligands was possible following the use of a solvent-free dry MALDI matrix application method employing finely ground dry α-cyano-4-hydroxycinnamic acid (CHCA). The D2 dopamine receptor antagonist 3,5-dichloro-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2-hydroxy-6-methoxybenzamide (raclopride) and the D1 dopamine receptor antagonist 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol (SCH 23390) were both detected at decreasing abundance at increasing period postdosing. Confirmation of the compound identifications and distributions was achieved by a combination of mass-to-charge ratio accurate mass, isotope distribution, and MS/MS fragmentation imaging directly from tissue sections (performed using MALDI TOF/TOF, MALDI q-TOF, and 12T MALDI-FT-ICR mass spectrometers). Quantitative data was obtained by comparing signal abundances from tissues to those obtained from quantitation control spots of the target compound applied to adjacent vehicle control tissue sections (analyzed during the same experiment). Following a single intravenous dose of raclopride (7.5 mg/kg), an average tissue concentration of approximately 60 nM was detected compared to 15 nM when the drug was dosed at 2 mg/kg, indicating a linear response between dose and detected abundance. SCH 23390 was established to have an average tissue concentration of approximately 15 μM following a single intravenous dose at 5 mg/kg. Both target compounds were also detected in kidney tissue sections when employing the same MSI methodology. This study illustrates that a MSI may well be readily applied to PET ligand research development when using a solvent-free dry matrix coating.

  • 8.
    Goodwin, Richard J. A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Borg, Daniel
    Langridge-Smith, Pat R. R.
    Harrison, David J.
    Mackay, C. Logan
    Iverson, Suzanne L.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Conductive carbon tape used for support and mounting of both whole animal and fragile heat-treated tissue sections for MALDI MS imaging and quantitation2012In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 75, no 16, p. 4912-4920Article in journal (Refereed)
    Abstract [en]

    Analysis of whole animal tissue sections by MALDI MS imaging (MSI) requires effective sample collection and transfer methods to allow the highest quality of in situ analysis of small or hard to dissect tissues. We report on the use of double-sided adhesive conductive carbon tape during whole adult rat tissue sectioning of carboxymethyl cellulose (CMC) embedded animals, with samples mounted onto large format conductive glass and conductive plastic MALDI targets, enabling MSI analysis to be performed on both TOF and FT-ICR MALDI mass spectrometers. We show that mounting does not unduly affect small molecule MSI detection by analyzing tiotropium abundance and distribution in rat lung tissues, with direct on-tissue quantitation achieved. Significantly, we use the adhesive tape to provide support to embedded delicate heat-stabilized tissues, enabling sectioning and mounting to be performed that maintained tissue integrity on samples that had previously been impossible to adequately prepare section for MSI analysis. The mapping of larger peptidomic molecules was not hindered by tape mounting samples and we demonstrate this by mapping the distribution of PEP-19 in both native and heat-stabilized rat brains. Furthermore, we show that without heat stabilization PEP-19 degradation fragments can detected and identified directly by MALDI MSI analysis.

    This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User's Guide to a New Technique for Biological and Biomedical Research.

  • 9.
    Goodwin, Richard J. A.
    et al.
    AstraZeneca R&D, Drug Safety & Metab, Cambridge CB4 OWG, England..
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mackay, C. Logan
    Univ Edinburgh, Sch Chem, Edinburgh, Midlothian, Scotland..
    Swales, John G.
    AstraZeneca R&D, Drug Safety & Metab, Cambridge CB4 OWG, England..
    Johansson, Maria K.
    Billger, Martin
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Iverson, Suzanne L.
    Exemplifying the Screening Power of Mass Spectrometry Imaging over Label-Based Technologies for Simultaneous Monitoring of Drug and Metabolite Distributions in Tissue Sections2016In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 21, no 2, p. 187-193Article in journal (Refereed)
    Abstract [en]

    Mass spectrometry imaging (MSI) provides pharmaceutical researchers with a suite of technologies to screen and assess compound distributions and relative abundances directly from tissue sections and offer insight into drug discovery-applicable queries such as blood-brain barrier access, tumor penetration/retention, and compound toxicity related to drug retention in specific organs/cell types. Label-free MSI offers advantages over label-based assays, such as quantitative whole-body autoradiography (QWBA), in the ability to simultaneously differentiate and monitor both drug and drug metabolites. Such discrimination is not possible by label-based assays if a drug metabolite still contains the radiolabel. Here, we present data exemplifying the advantages of MSI analysis. Data of the distribution of AZD2820, a therapeutic cyclic peptide, are related to corresponding QWBA data. Distribution of AZD2820 and two metabolites is achieved by MSI, which [C-14] AZD2820 QWBA fails to differentiate. Furthermore, the high mass-resolving power of Fourier transform ion cyclotron resonance MS is used to separate closely associated ions.

  • 10.
    Goodwin, Richard
    et al.
    AstraZeneca, Global DMPK, Cambridge, England..
    Swales, John
    AstraZeneca, Global DMPK, Cambridge, England..
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andrén, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Strittmatter, Nicola
    Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England..
    Takats, Zoltan
    Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England..
    Howes, Colin
    AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England..
    Taylor, Paula
    AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England..
    Ashton, Susan
    AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England..
    Jewsbury, Philip
    AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England..
    Barry, Simon T.
    AstraZeneca, Oncol iMED, Macclesfield, Cheshire, England..
    Imaging AZD1152HQPA Accurin (TM) nanoparticle accumulation in preclinical tumors2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75Article in journal (Other academic)
  • 11.
    Hulme, Heather E.
    et al.
    Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland..
    Meikle, Lynsey M.
    Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland..
    Wessel, Hannah
    Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland..
    Strittmatter, Nicole
    AstraZeneca, Milton Sci Pk, Cambridge CB4 0WG, England..
    Swales, John
    AstraZeneca, Milton Sci Pk, Cambridge CB4 0WG, England..
    Thomson, Carolyn
    Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland..
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nibbs, Robert J. B.
    Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland..
    Milling, Simon
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mackay, C. Logan
    Univ Edinburgh, Sch Chem, Edinburgh EH9 3FJ, Midlothian, Scotland..
    Dexter, Alex
    Natl Phys Lab, Teddington TW11 0LW, Middx, England..
    Bunch, Josephine
    Natl Phys Lab, Teddington TW11 0LW, Middx, England..
    Goodwin, Richard J. A.
    AstraZeneca, Milton Sci Pk, Cambridge CB4 0WG, England..
    Burchmore, Richard
    Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland..
    Wall, Daniel M.
    Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland..
    Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 2786Article in journal (Refereed)
    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.

  • 12.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wadensten, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurotoxin-Induced Neuropeptide Perturbations in Striatum of Neonatal Rats2013In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, no 4, p. 1678-1690Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial toxin β-N-methylamino-l-alanine (BMAA) is suggested to play a role in neurodegenerative disease. We have previously shown that although the selective uptake of BMAA in the rodent neonatal striatum does not cause neuronal cell death, exposure during the neonatal development leads to cognitive impairments in adult rats. The aim of the present study was to characterize the changes in the striatal neuropeptide systems of male and female rat pups treated neonatally (postnatal days 9-10) with BMAA (40-460 mg/kg). The label-free quantification of the relative levels of endogenous neuropeptides using mass spectrometry revealed that 25 peptides from 13 neuropeptide precursors were significantly changed in the rat neonatal striatum. The exposure to noncytotoxic doses of BMAA induced a dose-dependent increase of neurosecretory protein VGF-derived peptides, and changes in the relative levels of cholecystokinin, chromogranin, secretogranin, MCH, somatostatin and cortistatin-derived peptides were observed at the highest dose. In addition, the results revealed a sex-dependent increase in the relative level of peptides derived from the proenkephalin-A and protachykinin-1 precursors, including substance P and neurokinin A, in female pups. Because several of these peptides play a critical role in the development and survival of neurons, the observed neuropeptide changes might be possible mediators of BMAA-induced behavioral changes. Moreover, some neuropeptide changes suggest potential sex-related differences in susceptibility toward this neurotoxin. The present study also suggests that neuropeptide profiling might provide a sensitive characterization of the BMAA-induced noncytotoxic effects on the developing brain.

  • 13.
    Källback, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A Space Efficient Direct Access Data Compression Approach for Mass Spectrometry Imaging2018In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 6, p. 3676-3682Article in journal (Refereed)
    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.

  • 14.
    Källback, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    msIQuant - Quantitation Software for Mass Spectrometry Imaging Enabling Fast Access, Visualization, and Analysis of Large Data Sets2016In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 88, no 8, p. 4346-4353Article in journal (Refereed)
    Abstract [en]

    This paper presents msIQuant, a novel instrument- and manufacturer-independent quantitative mass spectrometry imaging software suite that uses the standardized open access data format imzML. Its data processing structure enables rapid image display and the analysis of very large data sets (>50 GB) without any data reduction. In addition, msIQuant provides many tools for image visualization including multiple interpolation methods, low intensity transparency display, and image fusion. It also has a quantitation function that automatically generates calibration standard curves from series of standards that can be used to determine the concentrations of specific analytes. Regions-of-interest in a tissue section can be analyzed based on a number of quantities including the number of pixels, average intensity, standard deviation of intensity, and median and quartile intensities. Moreover, the suite's export functions enable simplified postprocessing of data and report creation. We demonstrate its potential through several applications including the quantitation of small molecules such as drugs and neurotransmitters. The msIQuant suite is a powerful tool for accessing and evaluating very large data sets, quantifying drugs and endogenous compounds in tissue areas of interest, and for processing mass spectra and images.

  • 15.
    Källback, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Novel mass spectrometry imaging software assisting labeled normalization and quantitation of drugs and neuropeptides directly in tissue sections2012In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 75, no 16, p. 4941-4951Article in journal (Refereed)
    Abstract [en]

    MALDI MS imaging has been extensively used to produce qualitative distribution maps of proteins, peptides, lipids, small molecule pharmaceuticals and their metabolites directly in biological tissue sections. There is growing demand to quantify the amount of target compounds in the tissue sections of different organs. We present a novel MS imaging software including protocol for the quantitation of drugs, and for the first time, an endogenous neuropeptide directly in tissue sections. After selecting regions of interest on the tissue section, data is read and processed by the software using several available methods for baseline corrections, subtractions, denoising, smoothing, recalibration and normalization. The concentrations of in vivo administered drugs or endogenous compounds are then determined semi-automatically using either external standard curves, or by using labeled compounds, i.e., isotope labeled analogs as standards. As model systems, we have quantified the distribution of imipramine and tiotropium in the brain and lung of dosed rats. Substance P was quantified in different mouse brain structures, which correlated well with previously reported peptide levels. Our approach facilitates quantitative data processing and labeled standards provide better reproducibility and may be considered as an efficient tool to quantify drugs and endogenous compounds in tissue regions of interest.

  • 16.
    Lodén, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    An introduction to MS imaging in drug discovery and development2015In: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 7, no 20, p. 2621-2627Article in journal (Refereed)
    Abstract [en]

    A vital process in drug discovery and development is to assess the absorption, distribution, metabolism, excretion and toxicology of potentially therapeutic compounds in the body. The potential utility of MS imaging has been demonstrated in many studies focusing on molecules including peptides, proteins and lipids. However, MS imaging also permits the direct analysis of drugs and drug metabolites in tissue samples without requiring the use of target-specific labels or reagents. Here, a brief technical description of the technique is presented along with examples of its usefulness at different stages of the drug discovery and development process including absorption, distribution, metabolism, excretion and toxicology, and blood-brain barrier drug penetration investigations.

  • 17.
    Nilsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Forngren, B.
    Bjurström, S.
    Goodwin, R. J. A.
    Basmaci, E.
    Gustafsson, I.
    Annas, A.
    Hellgren, D.
    Svanhagen, A.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindberg, J.
    In Situ Mass Spectrometry Imaging and Ex Vivo Characterization of Renal Crystalline Deposits Induced in Multiple Preclinical Drug Toxicology Studies2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e47353-Article in journal (Refereed)
    Abstract [en]

    Drug toxicity observed in animal studies during drug development accounts for the discontinuation of many drug candidates, with the kidney being a major site of tissue damage. Extensive investigations are often required to reveal the mechanisms underlying such toxicological events and in the case of crystalline deposits the chemical composition can be problematic to determine. In the present study, we have used mass spectrometry imaging combined with a set of advanced analytical techniques to characterize such crystalline deposits in situ. Two potential microsomal prostaglandin E synthase 1 inhibitors, with similar chemical structure, were administered to rats over a seven day period. This resulted in kidney damage with marked tubular degeneration/regeneration and crystal deposits within the tissue that was detected by histopathology. Results from direct tissue section analysis by matrix-assisted laser desorption ionization mass spectrometry imaging were combined with data obtained following manual crystal dissection analyzed by liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical composition of the crystal deposits was successfully identified as a common metabolite, bisulphonamide, of the two drug candidates. In addition, an un-targeted analysis revealed molecular changes in the kidney that were specifically associated with the area of the tissue defined as pathologically damaged. In the presented study, we show the usefulness of combining mass spectrometry imaging with an array of powerful analytical tools to solve complex toxicological problems occurring during drug development.

  • 18.
    Nilsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Goodwin, Richard J. A.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vallianatou, Theodosia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Webborn, Peter J. H.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mass Spectrometry Imaging in Drug Development2015In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 87, no 3, p. 1437-1455Article, review/survey (Refereed)
  • 19.
    Nilsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Goodwin, Richard J. A.
    AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Cambridge CB4 0WG, England..
    Swales, John G.
    AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Cambridge CB4 0WG, England..
    Gallagher, Richard
    AstraZeneca R&D, Oncol DMPK, Innovat Med, Macclesfield SK10 4TF, Cheshire, England..
    Shankaran, Harish
    AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Waltham, MA 02451 USA..
    Sathe, Abhishek
    AstraZeneca R&D, Infect DMPK, Innovat Med, Waltham, MA 02451 USA..
    Pradeepan, Selvi
    AstraZeneca R&D, Infect DMPK, Innovat Med, Waltham, MA 02451 USA..
    Xue, Aixiang
    AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Waltham, MA 02451 USA..
    Keirstead, Natalie
    AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Waltham, MA 02451 USA..
    Sasaki, Jennifer C.
    AstraZeneca R&D, Drug Safety & Metab, Innovat Med, Waltham, MA 02451 USA..
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gupta, Anshul
    AstraZeneca R&D, Infect DMPK, Innovat Med, Waltham, MA 02451 USA.;AstraZeneca, Waltham, MA 02451 USA..
    Investigating Nephrotoxicity of Polymyxin Derivatives by Mapping Renal Distribution Using Mass Spectrometry Imaging2015In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 28, no 9, p. 1823-1830Article in journal (Refereed)
    Abstract [en]

    Colistin and polymyxin B are effective treatment options for Gram-negative resistant bacteria but are used as last-line therapy due to their dose-limiting nephrotoxicity. A critical factor in developing safer polymyxin analogues is understanding accumulation of the drugs and their metabolites, which is currently limited due to the lack of effective techniques for analysis of these challenging molecules. Mass spectrometry imaging (MSI) allows direct detection of targets (drugs, metabolites, and endogenous compounds) from tissue sections. The presented study exemplifies the utility of MSI by measuring the distribution of polymyxin B1, colistin, and polymyxin B nonapeptide (PMBN) within dosed rat kidney tissue sections. The label-free MSI analysis revealed that the nephrotoxic compounds (polymyxin B1 and colistin) preferentially accumulated in the renal cortical region. The less nephrotoxic analogue, polymyxin B nonapeptide, was more uniformly distributed throughout the kidney. In addition, metabolites of the dosed compounds were detected by MSI. Kidney homogenates were analyzed using LC/MS/MS to determine total drug exposure and for metabolite identification. To our knowledge, this is the first time such techniques have been utilized to measure the distribution of polymyxin drugs and their metabolites. By simultaneously detecting the distribution of drug and drug metabolites, MSI offers a powerful alternative to tissue homogenization analysis and label or antibody-based imaging.

  • 20.
    Nilsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Peric, Alexandra
    AstraZeneca Gothenburg, Cardiovasc & Metab Dis, Innovat Med & Early Dev, Gothenburg, Sweden..
    Strimfors, Marie
    AstraZeneca Gothenburg, Cardiovasc & Metab Dis, Innovat Med & Early Dev, Gothenburg, Sweden..
    Goodwin, Richard J. A.
    AstraZeneca Cambridge, Mass Spectrometry Imaging, Innovat Med & Early Dev, Drug Safety & Metab, Cambridge, England..
    Hayes, Martin A.
    AstraZeneca Gothenburg, Cardiovasc & Metab Dis, Innovat Med & Early Dev, Gothenburg, Sweden..
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hilgendorf, Constanze
    AstraZeneca Gothenburg, Cardiovasc & Metab Dis, Innovat Med & Early Dev, Gothenburg, Sweden.;AstraZeneca Gothenburg, Innovat Med & Early Dev, Drug Safety & Metab, Safety & ADME Translat Sci, Gothenburg, Sweden..
    Mass Spectrometry Imaging proves differential absorption profiles of well-characterised permeability markers along the crypt-villus axis2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6352Article in journal (Refereed)
    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.

  • 21.
    Nilsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Stroth, Nikolas
    Zhang, Xiaoqun
    Qi, Hongshi
    Fälth, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sköld, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hoyer, Daniel
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svenningsson, Per
    Neuropeptidomics of mouse hypothalamus after imipramine treatment reveal somatostatin as a potential mediator of antidepressant effects2012In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 62, no 1, p. 347-357Article in journal (Refereed)
    Abstract [en]

    Excessive activation of the hypothalamic pituitary adrenal (HPA) axis has been associated with numerous diseases, including depression, and the tricyclic antidepressant imipramine has been shown to suppress activity of the HPA axis. Central hypothalamic control of the HPA axis is complex and involves a number of neuropeptides released from multiple hypothalamic subnuclei. The present study was therefore designed to determine the effects of imipramine administration on the mouse hypothalamus using a peptidomics approach. Among the factors found to be downregulated after acute (one day) or chronic (21 days) imipramine administration were peptides derived from secretogranin 1 (chromogranin B) as well as peptides derived from cerebellin precursors. In contrast, peptides SRIF-14 and SRIF-28 (1-11) derived from somatostatin (SRIF, somatotropin release inhibiting factor) were significantly upregulated by imipramine in the hypothalamus. Because diminished SRIF levels have long been known to occur in depression, a second part of the study investigated the roles of individual SRIF receptors in mediating potential antidepressant effects. SRA880, an antagonist of the somatostatin-1 autoreceptor (sst1) which positively modulates release of endogenous SRIF, was found to synergize with imipramine in causing antidepressant-like effects in the tail suspension test. Furthermore, chronic co-administration of SRA880 and imipramine synergistically increased BDNF mRNA expression in the cerebral cortex. Application of SRIF or L054264, an sst2 receptor agonist, but not 1,803807, an sst4 receptor agonist, increased phosphorylation of CaMKII and GluR1 in cerebrocortical slices. Our present experiments thus provide evidence for antidepressant-induced upregulation of SRIF in the brain, and strengthen the notion that augmented SRIF expression and signaling may counter depressive-like symptoms.

  • 22. Nilsson, Carol L.
    et al.
    Berven, Frode
    Selheim, Frode
    Liu, Huiling
    Moskal, Joseph R.
    Kroes, Roger A.
    Sulman, Erik P.
    Conrad, Charles A.
    Lang, Frederick F.
    Andren, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carlsohn, Elisabet
    Lilja, Hans
    Malm, Johan
    Fenyoe, David
    Subramaniyam, Devipriya
    Wang, Xiangdong
    Gonzales-Gonzales, Maria
    Dasilva, Noelia
    Diez, Paula
    Fuentes, Manuel
    Vegvari, Akos
    Sjodin, Karin
    Welinder, Charlotte
    Laurell, Thomas
    Fehniger, Thomas E.
    Lindberg, Henrik
    Rezeli, Melinda
    Edula, Goutham
    Hober, Sophia
    Marko-Varga, Gyorgy
    Chromosome 19 Annotations with Disease Speciation: A First Report from the Global Research Consortium2013In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, no 1, p. 134-149Article in journal (Refereed)
    Abstract [en]

    A first research development progress report of the Chromosome 19 Consortium with members from Sweden, Norway, Spain, United States, China and India, a part of the Chromosome-centric Human Proteome Project (C-HPP) global initiative, is presented (http://www.c-hpp.org). From the chromosome 19 peptide-targeted library constituting 6159 peptides, a pilot study was conducted using a subset with 125 isotope-labeled peptides. We applied an annotation strategy with triple quadrupole, ESI-Qtrap, and MALDI mass spectrometry platforms, comparing the quality of data within and in between these instrumental set-ups. LC-MS conditions were outlined by multiplex assay developments, followed by MRM assay developments. SRM was applied to biobank samples, quantifying kallikrein 3 (prostate specific antigen) in plasma from prostate cancer patients. The antibody production has been initiated for more than 1200 genes from the entire chromosome 19, and the progress developments are presented. We developed a dedicated transcript microarray to serve as the mRNA identifier by screening cancer cell lines. NAPPA protein arrays were built to align with the transcript data with the Chromosome 19 NAPPA chip, dedicated to 90 proteins, as the first development delivery. We have introduced an IT-infrastructure utilizing a LIMS system that serves as the key interface for the research teams to share and explore data generated within the project. The cross-site data repository will form the basis for sample processing, including biological samples as well as patient samples from national Biobanks.

  • 23.
    Rossbach, Uwe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fälth, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhou, Qin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Andren, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    A quantitative peptidomic analysis of peptides related to the endogenous opioid and tachykinin systems in nucleus accumbens of rats following naloxone-precipitated morphine withdrawal2009In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 8, no 2, p. 1091-1098Article in journal (Refereed)
    Abstract [en]

    We have applied a recently developed label-free mass spectrometry based peptidomic approach to identify and quantify a variety of endogenous peptides from rat nucleus accumbens following withdrawal in naloxone-precipitated, morphine-dependent rats of two separate strains. We focused on maturated, partially processed and truncated peptides derived from the peptide precursors proenkephalin, prodynorphin and preprotachykinin. The expression of several identified peptides was dependent on strain and was affected during morphine withdrawal.

  • 24.
    Shariatgorji, Mohammadreza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fridjonsdottir, Elva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vallianatou, Theodosia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Källbäck, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Katan, Luay
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Sävmarker, Jonas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Mantas, Ioannis
    Karolinska Inst, Dept Clin Neurosci, Sect Neurol, Stockholm, Sweden.
    Zhang, Xiaoqun
    Karolinska Inst, Dept Clin Neurosci, Sect Neurol, Stockholm, Sweden.
    Bezard, Erwan
    Univ Bordeaux, Inst Malad Neurodegenerat, Bordeaux, France;CNRS, Inst Malad Neurodegenerat, Bordeaux, France.
    Svenningsson, Per
    Karolinska Inst, Dept Clin Neurosci, Sect Neurol, Stockholm, Sweden.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Comprehensive mapping of neurotransmitter networks by MALDI-MS imaging2019In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 16, no 10, p. 1021-1028Article in journal (Refereed)
    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.

  • 25.
    Shariatgorji, Mohammadreza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Goodwin, Richard J A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Källback, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schintu, Nicoletta
    Zhang, Xiaoqun
    Crossman, Alan R
    Bezard, Erwan
    Svenningsson, Per
    Andrén, Per E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Direct targeted quantitative molecular imaging of neurotransmitters in brain tissue sections2014In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 84, no 4, p. 697-707Article in journal (Refereed)
    Abstract [en]

    Current neuroimaging techniques have very limited abilities to directly identify and quantify neurotransmitters from brain sections. We have developed a molecular-specific approach for the simultaneous imaging and quantitation of multiple neurotransmitters, precursors, and metabolites, such as tyrosine, tryptamine, tyramine, phenethylamine, dopamine, 3-methoxytyramine, serotonin, GABA, glutamate, acetylcholine, and L-alpha-glycerylphosphorylcholine, in histological tissue sections at high spatial resolutions. The method is employed to directly measure changes in the absolute and relative levels ofneurotransmitters in specific brain structures in animal disease models and in response to drug treatments, demonstrating the power of mass spectrometry imaging in neuroscience.

  • 26.
    Shariatgorji, Mohammadreza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Goodwin, Richard J. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svenningsson, Per
    Schintu, Nicoletta
    Banka, Zoltan
    Kladni, Laszlo
    Hasko, Tibor
    Szabo, Andras
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Deuterated Matrix-Assisted Laser Desorption Ionization Matrix Uncovers Masked Mass Spectrometry Imaging Signals of Small Molecules2012In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 84, no 16, p. 7152-7157Article in journal (Refereed)
    Abstract [en]

    D-4-alpha-Cyano-4-hydroxycinnamic acid (D-4-CHCA) has been synthesized for use as a matrix for matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) and MALDI-MS imaging (MSI) of small molecule drugs and endogenous compounds. MALDI-MS analysis of small molecules has historically been hindered by interference from matrix ion clusters and fragment peaks that mask signals of low molecular weight compounds of interest. By using D-4-CHCA, the cluster and fragment peaks of CHCA, the most common matrix for analysis of small molecules, are shifted by + 4, + 8 and + 12 Da, which expose signals across areas of the previously concealed low mass range. Here, obscured MALDI-MS signals of a synthetic small molecule pharmaceutical, a naturally occurring isoquinoline alkaloid, and endogenous compounds including the neurotransmitter acetylcholine have been unmasked and imaged directly from biological tissue sections.

  • 27.
    Shariatgorji, Mohammadreza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Strittmatter, Nicole
    AstraZeneca, Drug Safety & Metab, Cambridge CB4 0WG, England..
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kallbäck, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alvarsson, Alexandra
    Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, S-17176 Stockholm, Sweden..
    Zhang, Xiaoqun
    Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, S-17176 Stockholm, Sweden..
    Vallianatou, Theodosia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svenningsson, Per
    Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, S-17176 Stockholm, Sweden..
    Goodwin, Richard J. A.
    AstraZeneca, Drug Safety & Metab, Cambridge CB4 0WG, England..
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 136, p. 129-138Article in journal (Refereed)
    Abstract [en]

    With neurological processes involving multiple neurotransmitters and neuromodulators, it is important to have the ability to directly map and quantify multiple signaling molecules simultaneously in a single analysis. By utilizing a molecular-specific approach, namely desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we demonstrated that the technique can be used to image multiple neurotransmitters and their metabolites (dopamine, dihydroxyphenylacetic acid, 3-methoxytyramine, serotonin, glutamate, glutamine, aspartate,gamma-aminobutyric acid, adenosine) as well as neuroactive drugs (amphetamine, sibutramine, fluvoxamine) and drug metabolites in situ directly in brain tissue sections. The use of both positive and negative ionization modes increased the number of identified molecular targets. Chemical derivatization by charge-tagging the primary amines of molecules significantly increased the sensitivity, enabling the detection of low abundant neurotransmitters and other neuroactive substances previously undetectable by MSI. The sensitivity of the imaging approach of neurochemicals has a great potential in many diverse applications in fields such as neuroscience, pharmacology, drug discovery, neurochemistry, and medicine.

  • 28.
    Sköld, Karl
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Marcus
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhang, Xiaqun
    Karolinska Institutet.
    Nydahl, Katarina
    Caprioli, Richard
    Vanderbilt university School of Medicine.
    Svenningsson, Per
    Karolinska Institutet.
    Andren, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Decreased Striatal Levels of PEP-19 Following MPTP Lesion in the Mouse.2006In: J Proteome Res, ISSN 1535-3893, Vol. 5, no 2, p. 262-269Article in journal (Refereed)
  • 29.
    Swales, John G.
    et al.
    AstraZeneca, IMED Biotech Unit, Pathol Drug Safety & Metab, Darwin Bldg,Cambridge Sci Pk,Milton Rd, Cambridge CB4 0WG, Cambs, England;Sheffield Hallam Univ, Ctr Mass Spectrometry Imaging, Biomol Res Ctr, Sheffield S1 1WB, S Yorkshire, England.
    Dexter, Alex
    Natl Ctr Excellence Mass Spectrometry Imaging NiC, Natl Phys Lab, Teddington TW11 0LW, Middx, England.
    Hamm, Gregory
    AstraZeneca, IMED Biotech Unit, Pathol Drug Safety & Metab, Darwin Bldg,Cambridge Sci Pk,Milton Rd, Cambridge CB4 0WG, Cambs, England.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Strittmatter, Nicole
    AstraZeneca, IMED Biotech Unit, Pathol Drug Safety & Metab, Darwin Bldg,Cambridge Sci Pk,Milton Rd, Cambridge CB4 0WG, Cambs, England.
    Michopoulos, Filippos
    AstraZeneca, IMED Biotech Unit, Biosci, Oncol, Cambridge CB4 0WG, England.
    Hardy, Christopher
    AstraZeneca, IMED Biotech Unit, Pathol Drug Safety & Metab, Darwin Bldg,Cambridge Sci Pk,Milton Rd, Cambridge CB4 0WG, Cambs, England.
    Morentin-Gutierrez, Pablo
    AstraZeneca, IMED Biotech Unit, Biosci, Oncol, Cambridge CB4 0WG, England.
    Mellor, Martine
    AstraZeneca, IMED Biotech Unit, Biosci, Oncol, Cambridge CB4 0WG, England.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Clench, Malcolm R.
    Sheffield Hallam Univ, Ctr Mass Spectrometry Imaging, Biomol Res Ctr, Sheffield S1 1WB, S Yorkshire, England.
    Bunch, Josephine
    Natl Ctr Excellence Mass Spectrometry Imaging NiC, Natl Phys Lab, Teddington TW11 0LW, Middx, England.
    Critchlow, Susan E.
    AstraZeneca, IMED Biotech Unit, Biosci, Oncol, Cambridge CB4 0WG, England.
    Goodwin, Richard J. A.
    AstraZeneca, IMED Biotech Unit, Pathol Drug Safety & Metab, Darwin Bldg,Cambridge Sci Pk,Milton Rd, Cambridge CB4 0WG, Cambs, England.
    Quantitation of Endogenous Metabolites in Mouse Tumors Using Mass-Spectrometry Imaging2018In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 10, p. 6051-6058Article in journal (Refereed)
    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.

  • 30. Swales, John G.
    et al.
    Tucker, James W.
    Strittmatter, Nicole
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cobice, Diego
    Clench, Malcolm R.
    Mackay, C. Logan
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Takats, Zoltan
    Webborn, Peter J. H.
    Goodwin, Richard J. A.
    Mass Spectrometry Imaging of Cassette-Dosed Drugs for Higher Throughput Pharmacokinetic and Biodistribution Analysis2014In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 86, no 16, p. 8473-8480Article in journal (Refereed)
    Abstract [en]

    Cassette dosing of compounds for preclinical drug plasma pharmacokinetic analysis has been shown to be a powerful strategy within the pharmaceutical industry for increasing throughput while decreasing the number of animals used. Presented here for the first time is data on the application of a cassette dosing strategy for label-free tissue distribution studies. The aim of the study was to image the spatial distribution of eight nonproprietary drugs (haloperidol, bufuralol, midazolam, clozapine, terfenadine, erlotinib, olanzapine, and moxifloxacin) in multiple tissues after oral and intravenous cassette dosing (four compounds per dose route). An array of mass spectrometry imaging technologies, including matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI), liquid extraction surface analysis tandem mass spectrometry (LESA-MS/MS), and desorption electrospray ionization mass spectrometry (DESI-MS) was used. Tissue analysis following intravenous and oral administration of discretely and cassette-dosed compounds demonstrated similar relative abundances across a range of tissues indicating that a cassette dosing approach was applicable. MALDI MSI was unsuccessful in detecting all of the target compounds; therefore, DESI MSL a complementary mass spectrometry imaging technique, was used to detect additional target compounds. In addition, by adapting technology used for tissue profiling (LESA-MS/MS) low spatial resolution mass spectrometry imaging (similar to 1 mm) was possible for all targets across all tissues. This study exemplifies the power of multiplatform MSI analysis within a pharmaceutical research and development (R&D) environment. Furthermore, we have illustrated that the cassette dosing approach can be readily applied to provide combined, label-free pharmacokinetic and drug distribution data at an early stage of the drug discovery/development process while minimizing animal usage.

  • 31.
    Vallianatou, Theodosia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fridjonsdottir, Elva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Källback, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schintu, Nicoletta
    Department of Neurology and Clinical Neuroscience, Karolinska Institutet, Stockholm, SE-17176, Sweden.
    Svenningsson, Per
    Department of Neurology and Clinical Neuroscience, Karolinska Institutet, Stockholm, SE-17176, Sweden.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition2019In: Neuropsychopharmacology, ISSN 0893-133X, Vol. 44, p. 2091-2098Article in journal (Refereed)
    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.

  • 32.
    Vallianatou, Theodosia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hulme, Heather
    Fridjonsdottir, Elva
    Svenningsson, Per
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Imaging age-induced perturbations of mitochondrial function, neurotransmission and lipid signaling in specific brain regionsManuscript (preprint) (Other academic)
  • 33.
    Vallianatou, Theodosia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Strittmatter, Nicole
    AstraZeneca, IMED Biotech Unit, Pathol Sci Drug Safety & Metab, Cambridge, England.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hamm, Gregory
    AstraZeneca, IMED Biotech Unit, Pathol Sci Drug Safety & Metab, Cambridge, England.
    Pereira, Marcela
    Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Källback, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svenningsson, Per
    Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Karlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Goodwin, Richard J. A.
    AstraZeneca, IMED Biotech Unit, Pathol Sci Drug Safety & Metab, Cambridge, England.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A mass spectrometry imaging approach for investigating how drug-drug interactions influence drug blood-brain barrier permeability2018In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 172, p. 808-816Article in journal (Refereed)
    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.

  • 34.
    Voigt, Thiemo
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Augustine, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Asan, Noor Badariah
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Perez, Mauricio D.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Ahlén, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signals and Systems Group.
    Teixeira, André
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signals and Systems Group.
    Hylamia, Sam
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Architecture and Computer Communication.
    Rohner, Christian
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Yan, Wenqing
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Nilsson, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mani, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Poster: Tumor sensing Privacy in In-Body networks2019Conference paper (Refereed)
  • 35.
    Voigt, Thiemo
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Architecture and Computer Communication. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Augustine, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Asan, Noor Badariah
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Perez, Mauricio D.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Ahlén, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signals and Systems Group.
    Teixeira, André
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signals and Systems Group.
    Hylamia, Sam
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Architecture and Computer Communication.
    Rohner, Christian
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Yan, Wenqing
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computer Systems.
    Nilsson, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mani, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Short Talk: LifeSec - Don't Hack my Body2019Conference paper (Refereed)
  • 36.
    Zhang, Xiaoqun
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Mantas, Ioannis
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Alvarsson, Alexandra
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Yoshitake, Takashi
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacol Neurochem, Solna, Sweden..
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Biomolecular Mass Spectrometry Imaging, National Resource for Mass Spectrometry Imaging, Uppsala, Sweden.
    Pereira, Marcela
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Biomol Mass Spectrometry Imaging, Natl Resource Mass Spectrometry Imaging, Uppsala, Sweden..
    Kehr, Jan
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacol Neurochem, Solna, Sweden..
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Biomol Mass Spectrometry Imaging, Natl Resource Mass Spectrometry Imaging, Uppsala, Sweden..
    Millan, Mark J.
    Ctr Rech Croissy, Ctr Therapeut Innovat CNS, Inst Rech Servier, Paris, France..
    Chergui, Karima
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Mol Neurophysiol, Solna, Sweden..
    Svenningsson, Per
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or beta-Phenylethylamine2018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 166Article in journal (Refereed)
    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.

1 - 36 of 36
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