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Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. (Medical mass spectrometry imaging)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. (Medical mass spectrometry imaging)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. (Medical mass spectrometry imaging)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. (Medical mass spectrometry imaging)ORCID iD: 0000-0002-3779-3556
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2019 (English)In: Neuropsychopharmacology, ISSN 0893-133X, Vol. 44, p. 2091-2098Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
2019. Vol. 44, p. 2091-2098
Keywords [en]
mass spectrometry imaging, acetylcholine, retrosplenial cortex, tacrine, aging
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-392312DOI: 10.1038/s41386-019-0397-5ISI: 000490174900013PubMedID: 31009936OAI: oai:DiVA.org:uu-392312DiVA, id: diva2:1347882
Funder
Swedish Research Council, 2018-03320Swedish Research Council, 2018-05501EU, FP7, Seventh Framework Programme, 607517The Swedish Brain FoundationSwedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceAvailable from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-11-08Bibliographically approved
In thesis
1. Advanced Mass Spectrometry Imaging in Neuropharmacology
Open this publication in new window or tab >>Advanced Mass Spectrometry Imaging in Neuropharmacology
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
mass spectrometry imaging, neuropharmacology, blood brain barrier, drug-drug interactions, aging, tacrine
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-392320 (URN)978-91-513-0739-8 (ISBN)
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

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