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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