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Advanced Mass Spectrometry Imaging in Neuropharmacology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Medical mass spectrometry imaging)
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 278
Keywords [en]
mass spectrometry imaging, neuropharmacology, blood brain barrier, drug-drug interactions, aging, tacrine
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-392320ISBN: 978-91-513-0739-8 (print)OAI: oai:DiVA.org:uu-392320DiVA, id: diva2:1347938
Public defence
2019-10-18, Room B42, Uppsala biomedicinska centrum (BMC) Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-09-27 Created: 2019-09-02 Last updated: 2019-10-15
List of papers
1. A mass spectrometry imaging approach for investigating how drug-drug interactions influence drug blood-brain barrier permeability
Open this publication in new window or tab >>A mass spectrometry imaging approach for investigating how drug-drug interactions influence drug blood-brain barrier permeability
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2018 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 172, p. 808-816Article in journal (Refereed) Published
Abstract [en]

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

Keywords
Mass spectrometry imaging, Blood-brain barrier, Drug-drug interactions, Elacridar, Loperamide, Propranolol
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-353358 (URN)10.1016/j.neuroimage.2018.01.013 (DOI)000430364100067 ()29329980 (PubMedID)
Funder
Swedish Research Council, 2013-3105]Swedish Research Council, 2014-6215]Swedish Foundation for Strategic Research , RIF14-0078]AstraZenecaEU, FP7, Seventh Framework Programme, 607517The Swedish Brain FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-06-12 Created: 2018-06-12 Last updated: 2019-09-02Bibliographically approved
2. Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition.
Open this publication in new window or tab >>Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition.
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2019 (English)In: Neuropsychopharmacology, ISSN 0893-133X, Vol. 0, p. 1-8Article in journal (Refereed) Published
Abstract [en]

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

Keywords
mass spectrometry imaging, acetylcholine, retrosplenial cortex, tacrine, aging
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-392312 (URN)10.1038/s41386-019-0397-5 (DOI)
Available from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-09-02
3. Imaging age-induced perturbations of mitochondrial function, neurotransmission and lipid signaling in specific brain regions
Open this publication in new window or tab >>Imaging age-induced perturbations of mitochondrial function, neurotransmission and lipid signaling in specific brain regions
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-392314 (URN)
Available from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-09-02
4. Imaging aging effects on the catecholamine, serotonin, and histamine neurotransmitter systems in specific brain regions
Open this publication in new window or tab >>Imaging aging effects on the catecholamine, serotonin, and histamine neurotransmitter systems in specific brain regions
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-392315 (URN)
Available from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-09-02

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