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Imaging aging effects on the catecholamine, serotonin, and histamine neurotransmitter systems in specific brain regions
(Medical mass spectrometry imaging)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab. (Medical mass spectrometry imaging)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab. (Medical mass spectrometry imaging)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab. (Medical mass spectrometry imaging)
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-392315OAI: oai:DiVA.org:uu-392315DiVA, id: diva2:1347894
Tillgänglig från: 2019-09-02 Skapad: 2019-09-02 Senast uppdaterad: 2019-09-02
Ingår i avhandling
1. Advanced Mass Spectrometry Imaging in Neuropharmacology
Öppna denna publikation i ny flik eller fönster >>Advanced Mass Spectrometry Imaging in Neuropharmacology
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Mass spectrometry imaging (MSI) has emerged as a valuable approach for mapping multiple molecular species in sections of diverse tissues. It enables simultaneous detection of numerous compounds (from neurotransmitters to small proteins) in the brain at relatively high lateral resolution (>5 μm) on a routine basis. Matrix-assisted laser desorption/ionization (MALDI)-MSI and desorption electrospray ionization (DESI)-MSI are the most widely applied MSI techniques in tissue distribution studies. Recent advances in MSI instruments and software allow quantitative analysis of large numbers of compounds with high mass accuracy and high mass resolving power. Thus, in studies this thesis is based upon, MSI technology was used to address several challenging aspects of neuropharmacology. Restricted passage of potentially neuroactive substances into the brain, unpredictable multi-target effects, and the complexity of the central nervous system (CNS) physiology, are major obstacles in the development of efficient drugs. The simultaneous investigation of drugs’ delivery to the brain and potential effects on several CNS pathways in specific brain regions is, therefore, highly important. In addition, localization information is required for more comprehensive insights into CNS responses to both pharmaceutical agents and biological processes such as aging.

MSI-based analysis of the transport of two selected drugs into the brain demonstrated effects of efflux membrane proteins on their distributions in the brain. The MDR1 substrate loperamide was found to localize specifically in the choroid plexus, indicating low brain entrance. In addition, MSI uncovered drug-drug interactions at the blood-brain barrier involving MDR1 inhibition. The technology was further used to explore neurochemical alterations induced by aging and acetylcholinesterase inhibition. First, MSI revealed that the cholinergic system’s responsivity in the retrosplenial cortex, a post-cingulate cortical area highly involved in cognition, to acetylcholinesterase inhibition significantly declined with age. Subsequently, simultaneous investigation of multiple brain metabolic pathways in specific brain areas with multivariate data analysis techniques demonstrated age-induced alterations in mitochondrial function, lipid signaling, and acetylcholine metabolism. Finally, MSI unveiled age-induced alterations in levels and distributions of the monoaminergic neurotransmitters and their metabolites in particular brain areas such as the ventral pallidum, caudate putamen, hippocampus, and cortical substructures. Age- and region-specific effects of acetylcholinesterase inhibition on the neurotransmitter systems were also detected. In conclusion, the studies provided novel insights into important brain pharmacokinetic and pharmacodynamic phenomena using advanced MSI techniques, as described and discussed in this thesis.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 68
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 278
Nyckelord
mass spectrometry imaging, neuropharmacology, blood brain barrier, drug-drug interactions, aging, tacrine
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-392320 (URN)978-91-513-0739-8 (ISBN)
Disputation
2019-10-18, Room B42, Uppsala biomedicinska centrum (BMC) Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-09-27 Skapad: 2019-09-02 Senast uppdaterad: 2019-10-15

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Vallianatou, TheodosiaShariatgorji, MohammadrezaNilsson, AnnaAndrén, Per E.

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Fridjonsdottir, ElvaVallianatou, TheodosiaShariatgorji, MohammadrezaNilsson, AnnaAndrén, Per E.
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Institutionen för farmaceutisk biovetenskapScience for Life Laboratory, SciLifeLabInstitutionen för läkemedelskemi
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