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Långström, Bengt
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Publications (10 of 165) Show all publications
Li, J., Kumar, A., Långström, B., Nordberg, A. & Ågren, H. (2023). Insight into the Binding of First- and Second-Generation PET Tracers to 4R and 3R/4R Tau Protofibrils. ACS Chemical Neuroscience, 14(18), 3528-3539
Open this publication in new window or tab >>Insight into the Binding of First- and Second-Generation PET Tracers to 4R and 3R/4R Tau Protofibrils
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2023 (English)In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 14, no 18, p. 3528-3539Article in journal (Refereed) Published
Abstract [en]

Primary supranuclear palsy (PSP) is a rare neurodegenerative disease that perturbs body movement, eye movement, and walking balance. Similar to Alzheimer’s disease (AD), the abnormal aggregation of tau fibrils in the central neuronal and glial cells is a major hallmark of PSP disease. In this study, we use multiple approaches, including docking, molecular dynamics, and metadynamics simulations, to investigate the binding mechanism of 10 first- and second-generations of PET tracers for PSP tau and compare their binding in cortical basal degeneration (CBD) and AD tauopathies. Structure–activity relationships, binding preferences, the nature of ligand binding in terms of basic intermolecular interactions, the role of polar/charged residues, induced-fit mechanisms, grove closures, and folding patterns for the binding of these tracers in PSP, CBD, and AD tau fibrils are evaluated and discussed in detail in order to build a holistic picture of what is essential for the binding and also to rank the potency of the different tracers. For example, we found that the same tracer shows different binding preferences for the surface sites of tau fibrils that are intrinsically distinct in the folding patterns. Results from the metadynamics simulations predict that PMPBB3 and PBB3 exhibit the strongest binding free energies onto the Q276[I277]I278, Q351[S352]K353, and N368[K369]K370 sites of PSP than the other explored tracers, indicating a solid preference for vdW and cation−π interactions. Our results also reproduced known preferences of tracers, namely, that MK6240 binds better to AD tau than CBD tau and PSP tau and that CBD2115, PI2620, and PMPBB3 are 4R tau binders. These findings fill in the well-sought-after knowledge gap in terms of these tracers’ potential binding mechanisms and will be important for the design of highly selective novel PET tracers for tauopathies.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
Keywords
4R tau fibrils, metadynamics, positron emission tomography tracer, free energy surface, Alzheimer disease, molecular dynamics
National Category
Health Sciences Biophysics
Identifiers
urn:nbn:se:uu:diva-511105 (URN)10.1021/acschemneuro.3c00437 (DOI)001063848300001 ()37639522 (PubMedID)
Funder
Swedish Research Council, 2017-06086
Available from: 2023-09-07 Created: 2023-09-07 Last updated: 2023-11-07Bibliographically approved
Baidya, A. T. K., Das, B., Devi, B., Långström, B., Ågren, H., Darreh-Shori, T. & Kumar, R. (2023). Mechanistic Insight into the Inhibition of Choline Acetyltransferase by Proton Pump Inhibitors. ACS Chemical Neuroscience, 14(4), 749-765
Open this publication in new window or tab >>Mechanistic Insight into the Inhibition of Choline Acetyltransferase by Proton Pump Inhibitors
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2023 (English)In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 14, no 4, p. 749-765Article in journal (Refereed) Published
Abstract [en]

Various pharmacoepidemiological investigational studies have indicated that Proton Pump Inhibitors (PPIs) may increase the likelihood of developing Alzheimer's disease (AD) and non-AD related dementias. Previously, we have reported the inhibition of the acetylcholine biosynthesizing enzyme choline acetyltransferase (ChAT) by PPIs, for which omeprazole, lansoprazole, and pantoprazole exhibited IC50 values of 0.1, 1.5, and 5.3 mu M, respectively. In this study we utilize a battery of computational tools to perceive a mechanistic insight into the molecular interaction of PPIs with the ChAT binding pocket that may further help in designing novel ChAT ligands. Various in-silico tools make it possible for us to elucidate the binding interaction, conformational stability, and dynamics of the protein-ligand complexes within a 200 ns time frame. Further, the binding free energies for the PPI-ChAT complexes were explored. The results suggest that the PPIs exhibit equal or higher binding affinity toward the ChAT catalytic tunnel and are stable throughout the simulated time and that the pyridine ring of the PPIs interacts primarily with the catalytic residue His324. A free energy landscape analysis showed that the folding process was linear, and the residue interaction network analysis can provide insight into the roles of various amino acid residues in stabilization of the PPIs in the ChAT binding pocket. As a major factor for the onset of Alzheimer's disease is linked to cholinergic dysfunction, our previous and the present findings give clear insight into the PPI interaction with ChAT. The scaffold can be further simplified to develop novel ChAT ligands, which can also be used as ChAT tracer probes for the diagnosis of cholinergic dysfunction and to initiate timely therapeutic interventions to prevent or delay the progression of AD.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
Keywords
proton pump inhibitors, choline-acetyltransferase, Alzheimer?s disease, dementia, neurodegenerative disorder, molecular docking, molecular dynamics, MM-PBSA, PET-ligands
National Category
Biochemistry and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:uu:diva-501788 (URN)10.1021/acschemneuro.2c00738 (DOI)000930589300001 ()36749117 (PubMedID)
Funder
Swedish Research Council, 2018-05973
Available from: 2023-05-16 Created: 2023-05-16 Last updated: 2023-08-28Bibliographically approved
Mallapura, H., Ovdiichuk, O., Jussing, E., Thuy, T. A., Piatkowski, C., Tanguy, L., . . . Nag, S. (2023). Microfluidic-based production of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC using the cassette-based iMiDEV™ microfluidic radiosynthesizer. EJNMMI Radiopharmacy and Chemistry, 8(1), Article ID 42.
Open this publication in new window or tab >>Microfluidic-based production of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC using the cassette-based iMiDEV™ microfluidic radiosynthesizer
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2023 (English)In: EJNMMI Radiopharmacy and Chemistry, E-ISSN 2365-421X, Vol. 8, no 1, article id 42Article in journal (Refereed) Published
Abstract [en]

Background The demand for Ga-68-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, Ga-68-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([Ga-68]Ga-FAPI-46) in late-phase studies, whereas [Ga-68]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach.Results Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 +/- 5% for [Ga-68]Ga-FAPI-46 and 46 +/- 7% for [Ga-68]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC were 98.2 +/- 0.2% and 98.4 +/- 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including Ga-68 trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers.Conclusions The microfluidic-based approach enabled the implementation of radiosynthesis of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC on the iMiDEV (TM) microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2-3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a similar microfluidic iMiDEV module at a different research center for the synthesis of [Ga-68]Ga-FAPI-46 with limited runs. Our study demonstrated the potential of microfluidic methods for efficient and reliable radiometal-based radiopharmaceutical synthesis, contributing valuable insights for future advancements in this field and paving the way for routine clinical applications in the near future.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Positron emission tomography (PET), Radiopharmaceuticals, Microfluidics, iMiDEV, [Ga-68]Ga-FAPI-46, [Ga-68]Ga-DOTA-TOC, Radiolabeling, Dose-on-demand (DOD), Radiotracers
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-519144 (URN)10.1186/s41181-023-00229-9 (DOI)001125147900001 ()38091157 (PubMedID)
Funder
Karolinska Institute
Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-08Bibliographically approved
Nag, S., Miranda-Azpiazu, P., Jia, Z., Datta, P., Arakawa, R., Moein, M. M., . . . Halldin, C. (2022). Development of C-11-Labeled ASEM Analogues for the Detection of Neuronal Nicotinic Acetylcholine Receptors (alpha 7-nAChR). ACS Chemical Neuroscience, 13(3), 352-362
Open this publication in new window or tab >>Development of C-11-Labeled ASEM Analogues for the Detection of Neuronal Nicotinic Acetylcholine Receptors (alpha 7-nAChR)
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2022 (English)In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 13, no 3, p. 352-362Article in journal (Refereed) Published
Abstract [en]

The homo-pentameric alpha 7 receptor is one of the major types of neuronal nicotinic acetylcholine receptors (alpha 7nAChRs) related to cognition, memory formation, and attention processing. The mapping of alpha 7-nAChRs by PET pulls a lot of attention to realize the mechanism and development of CNS diseases such as AD, PD, and schizophrenia. Several PET radioligands have been explored for the detection of the alpha 7-nAChR. F-18-ASEM is the most functional for in vivo quantification of alpha 7-nAChRs in the human brain. The first aim of this study was to initially use results from in silico and machine learning techniques to prescreen and predict the binding energy and other properties of ASEM analogues and to interpret these properties in terms of atomic structures using F-18-ASEM as a lead structure, and second, to label some selected candidates with carbon-11/hydrogen-3 (C-11/H-3) and to evaluate the binding properties in vitro and in vivo using the labeled candidates. In silico predictions are obtained from perturbation free-energy calculations preceded by molecular docking, molecular dynamics, and metadynamics simulations. Machine learning techniques have been applied for the BBB and P-gp-binding properties. Six analogues of ASEM were labeled with C-11, and three of them were additionally labeled with H-3. Binding properties were further evaluated using autoradiography (ARG) and PET measurements in non-human primates (NHPs). Radiometabolites were measured in NHP plasma. All six compounds were successfully synthesized. Evaluation with ARG showed that C-11-Kln83 was preferably binding to the alpha 7-nAChR. Competition studies showed that 80% of the total binding was displaced. Further ARG studies using H-3-KIn-83 replicated the preliminary results. In the NHP PET study, the distribution pattern of C-11-KIn-83 was similar to other alpha 7 nAChR PET tracers. The brain uptake was relatively low and increased by the administration of tariquidar, indicating a substrate of P-gp. The ASEM blocking study showed that C-11-KIn-83 specifically binds to alpha 7 nAChRs. Preliminary in vitro evaluation of KIn-83 by ARG with both C-11 and H-3 and in vivo evaluation in NHP showed favorable properties for selectively imaging alpha 7-nAChRs, despite a relatively low brain uptake.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2022
Keywords
alpha 7-nAChR, PET, non-human primate, autoradiography, radiometabolites, in vivo, in vitro
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-484828 (URN)10.1021/acschemneuro.1c00730 (DOI)000743728000001 ()35020351 (PubMedID)
Funder
Swedish Foundation for Strategic Research, RB13-0192
Available from: 2022-09-19 Created: 2022-09-19 Last updated: 2023-08-28Bibliographically approved
Mallapura, H., Tanguy, L., Långström, B., Le Meunier, L., Halldin, C. & Nag, S. (2022). Production of [C-11]Carbon Labelled Flumazenil and L-Deprenyl Using the iMiDEV (TM) Automated Microfluidic Radiosynthesizer. Molecules, 27(24), Article ID 8843.
Open this publication in new window or tab >>Production of [C-11]Carbon Labelled Flumazenil and L-Deprenyl Using the iMiDEV (TM) Automated Microfluidic Radiosynthesizer
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2022 (English)In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 27, no 24, article id 8843Article in journal (Refereed) Published
Abstract [en]

In the last decade, microfluidic techniques have been explored in radiochemistry, and some of them have been implemented in preclinical production. However, these are not suitable and reliable for preparing different types of radiotracers or dose-on-demand production. A fully automated iMiDEV (TM) microfluidic radiosynthesizer has been introduced and this study is aimed at using of the iMiDEV (TM) radiosynthesizer with a microfluidic cassette to produce [C-11]flumazenil and [C-11]L-deprenyl. These two are known PET radioligands for benzodiazepine receptors and monoamine oxidase-B (MAO-B), respectively. Methods were successfully developed to produce [C-11]flumazenil and [C-11]L-deprenyl using [C-11]methyl iodide and [C-11]methyl triflate, respectively. The final products 1644 +/- 504 MBq (n = 7) and 533 +/- 20 MBq (n = 3) of [C-11]flumazenil and [C-11]L-deprenyl were produced with radiochemical purities were over 98% and the molar activity for [C-11]flumazenil and [C-11]L-deprenyl was 1912 +/- 552 GBq/mu mol, and 1463 +/- 439 GBq/mu mol, respectively, at the end of synthesis. All the QC tests complied with the European Pharmacopeia. Different parameters, such as solvents, bases, methylating agents, precursor concentration, and different batches of cassettes, were explored to increase the radiochemical yield. Synthesis methods were developed using 3-5 times less precursor than conventional methods. The fully automated iMiDEV (TM) microfluidic radiosynthesizer was successfully applied to prepare [C-11]flumazenil and [C-11]L-deprenyl.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
PET radiotracers, microfluidics, iMiDEV (TM), [C-11]flumazenil, [C-11]L-deprenyl, radiosynthesis, microfluidic cassette, dose-on-demand (DOD)
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-495396 (URN)10.3390/molecules27248843 (DOI)000904429900001 ()36557975 (PubMedID)
Available from: 2023-01-31 Created: 2023-01-31 Last updated: 2023-08-28Bibliographically approved
Ovdiichuk, O., Mallapura, H., Pineda, F., Hourtané, V., Långström, B., Halldin, C., . . . Collet, C. (2021). Implementation of iMiDEV™, a new fully automated microfluidic platform for radiopharmaceutical production. Lab on a Chip, 21(11), 2272-2282
Open this publication in new window or tab >>Implementation of iMiDEV™, a new fully automated microfluidic platform for radiopharmaceutical production
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2021 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 21, no 11, p. 2272-2282Article in journal (Refereed) Published
Abstract [en]

iMiDEV™ microfluidic system is a new automated tool for a small-scale production of radiopharmaceuticals. This new radiochemistry module utilizes microfluidic cassettes capable of producing diversified radiopharmaceuticals in liquid phase reactions in an automated synthesizer. The user interface is intuitive and designed to give the operator all the information required and to allow driving the synthesis either manually or fully automatically. In this work, we have demonstrated liquid phase reaction and presented the first results of an efficient fully automated [18F]NaF radiosynthesis on the iMiDEV™ platform. Different parameters such as a type of cyclotron targets, initial activity, concentration and volume of the fluoride-18 targetry have been investigated in order to elaborate the optimised radiolabelling of the ligand. Single and double sodium [18F]fluoride synthesis procedures have been successfully developed using two chambers of the cassette. A single-dose of radiotracer was produced in an average radiochemical yield of 87% (decay corrected) within 8 min and quality control tests were performed as per European Pharmacopoeia.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2021
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-454491 (URN)10.1039/d1lc00148e (DOI)000645116400001 ()33912890 (PubMedID)
Funder
European Regional Development Fund (ERDF)
Note

Title in Web of Science: Implementation of iMiDEV (TM), a new fully automated microfluidic platform for radiopharmaceutical production

Available from: 2021-09-29 Created: 2021-09-29 Last updated: 2024-01-15Bibliographically approved
Zhou, Y., Kuang, G., Li, J., Halldin, C., Nordberg, A., Långström, B., . . . Ågren, H. (2021). In silico studies of ASEM analogues targeting alpha 7-nAChR and experimental verification. RSC Advances, 11(7), 3942-3951
Open this publication in new window or tab >>In silico studies of ASEM analogues targeting alpha 7-nAChR and experimental verification
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2021 (English)In: RSC Advances, E-ISSN 2046-2069, Vol. 11, no 7, p. 3942-3951Article in journal (Refereed) Published
Abstract [en]

The alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) is implicated in a variety of neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease (AD) and schizophrenia. The progress of these disorders can be studied using positron emission tomography (PET) with radiotracers for alpha 7-nAChR. [F-18]ASEM and [F-18] para-ASEM (also referred to as [F-18]DBT-10) are novel and potent alpha 7-nAChR PET radiotracers which have successfully been used in human subjects and nonhuman primates, though further improvement of them is still a pressing task in the community of neurodegeneration research. In this work, we demonstrate the use of modern in silico techniques to predict the binding modes, binding strengths, and residence times for molecular PET tracers binding to proteins, using ASEM and DBT-10 as a showcase of the predictive and interpretational power of such techniques, in particular free energy perturbation theory. The corresponding compounds were synthesized and further tested by in vitro binding experiment for validation. Encouragingly, our in silico modeling can correctly predict the binding affinities of the ASEM analogues. The structure-activity relationships for the ortho- and para-substitutions are well explained at the atomistic level and provide structure-based guiding for the future development of PET tracers for alpha 7-nAChR. A discussion is presented on the complementary use of in silico rational methods based on atomic and electronic principles for in vitro characterization of PET tracers.

Place, publisher, year, edition, pages
Royal Society of ChemistryROYAL SOC CHEMISTRY, 2021
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-437881 (URN)10.1039/d0ra10435c (DOI)000615282100018 ()
Funder
Swedish Foundation for Strategic Research , RB13-0192Swedish Research Council, 2017-06086
Available from: 2021-03-22 Created: 2021-03-22 Last updated: 2024-01-15Bibliographically approved
Eriksson, O., Långström, B. & Antoni, G. (2021). News ways of understanding the complex biology of diabetes using PET. Nuclear Medicine and Biology, 92, 65-71
Open this publication in new window or tab >>News ways of understanding the complex biology of diabetes using PET
2021 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 92, p. 65-71Article, review/survey (Refereed) Published
Abstract [en]

The understanding of metabolic disease and diabetes on a molecular level has increased significantly due to the recent advances in molecular biology and biotechnology. However, in vitro studies and animal models do not always translate to the human disease, perhaps illustrated by the failure of many drug candidates in the clinical phase. Non-invasive biomedical imaging techniques such as Positron Emission Tomography (PET) offer tools for direct visualization and quantification of molecular processes in humans. Developments in this area potentially enable longitudinal in vivo studies of receptors and processes involved in diabetes guiding drug development and diagnosis in the near future. This mini-review focuses on describing the overall perspective of how PET can be used to increase our understanding and improve treatment of diabetes. The methodological aspects and future developments and challenges are highlighted.

Place, publisher, year, edition, pages
ElsevierELSEVIER SCIENCE INC, 2021
Keywords
PET, Receptor occupancy, Target engagement, Target distribution, Diabetes, Beta cell mass, Hormone receptors, Tracer development
National Category
Radiology, Nuclear Medicine and Medical Imaging Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-454609 (URN)10.1016/j.nucmedbio.2020.04.004 (DOI)000616652500008 ()32387114 (PubMedID)
Funder
Swedish Child Diabetes FoundationDiabetesfonden
Available from: 2021-09-30 Created: 2021-09-30 Last updated: 2024-01-15Bibliographically approved
Eriksson, J., Antoni, G., Långström, B. & Itsenko, O. (2021). The development of 11C-carbonylation chemistry: A systematic view. Nuclear Medicine and Biology, 92, 115-137
Open this publication in new window or tab >>The development of 11C-carbonylation chemistry: A systematic view
2021 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 92, p. 115-137Article, review/survey (Refereed) Published
Abstract [en]

The prospects for using carbon-11 labelled compounds in molecular imaging has improved with the development of diverse synthesis methods, including C-11-carbonylations and refined techniques to handle [C-11]carbon monoxide at a nanomole scale. Facilitating biological research and molecular imaging was the driving force when [C-11]carbon monoxide was used in the first in vivo application with carbon-11 in human (1945) and when [C-11]carbon monoxide was used for the first time as a chemical reagent in the synthesis of [C-11]phosgene (1978). This review examines a rich plethora of labelled compounds synthesized from [C-11]carbon monoxide, their chemistry and use in molecular imaging. While the strong development of the C-11-carbonylation chemistry has expanded the carbon-11 domain considerably, it could be argued that the number of C-11-carbonyl compounds entering biological investigations should be higher. The reason for this may partly be the lack of commercially available synthesis instruments designed for C-11-carbonylations. But as this review shows, novel and greatly simplified methods to handle [C-11]carbon monoxide have been developed. The next important challenge is to make full use of these technologies and synthesis methods in PET research. When there is a PET-tracer that meets a more general need, the incentive to implement C-11-carbonylation protocols will increase.

Place, publisher, year, edition, pages
ElsevierELSEVIER SCIENCE INC, 2021
Keywords
C-11-carbonylation, Positron emission tomography, PET, Carbon-11, Carbon monoxide
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-454638 (URN)10.1016/j.nucmedbio.2020.02.005 (DOI)000616652500014 ()32147168 (PubMedID)
Available from: 2021-09-30 Created: 2021-09-30 Last updated: 2024-01-15Bibliographically approved
Kumar, A., Kumar, R., Flanagan, J., Långström, B., Björndahl, L. & Darreh-Shori, T. (2020). Esomeprazole reduces sperm motility index by targeting the spermic cholinergic machinery: A mechanistic study for the association between use of proton pump inhibitors and reduced sperm motility index. Biochemical Pharmacology, 182, Article ID 114212.
Open this publication in new window or tab >>Esomeprazole reduces sperm motility index by targeting the spermic cholinergic machinery: A mechanistic study for the association between use of proton pump inhibitors and reduced sperm motility index
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2020 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 182, article id 114212Article in journal (Refereed) Published
Abstract [en]

Recent studies have linked prolonged use of the most commonly prescribed proton pump inhibitors (PPIs) with declined human sperm function and infertility. Here, we report for the first time the most plausible underlying mechanism for this unwarranted secondary mode of action. We followed up on a recent serendipitous discovery in our laboratory regarding PPIs' off-target action and performed detailed pharmacodynamic analyses by combining in silico and in vitro studies to determine the off-target effect of one of the most commonly used PPI, esomeprazole, on the key human acetylcholine biosynthesizing enzyme, choline acetyltransferase (ChAT; EC 2.3.1.6). A pivotal enzyme in the spermic cholinergic system that governs the sperm motility, concentration and quality. Our results were conclusive and showed that both the racemic form, omeprazole and its pure S-enantiomer, esomeprazole, acted as potent mixed-competitive inhibitor of human ChAT with a global inhibition constant (Ki) of 88 nM (95%CI: 10-167 nM) for esomeprazole and 178 nM (95%CI: 140-230 nM) for the racemic drug omeprazole. Most importantly, esomeprazole substantially reduces both total number of motile sperm (by 36%, p < 0.001; and 21% p < 0.0001, at 10 and 100 nM, respectively) as well as the total number of sperm with progressive motility (by 42% p < 0.0016 and by 26% p < 0.0001, respectively) after 60 min relative to 20 min incubation in our ex vivo functional assay performed on ejaculated human sperm. In conclusion, this study presents a completely new perspective regarding PPIs secondary mode of action/unwarranted side effects and calls for further mechanistic and larger clinical studies to elucidate the role of PPIs in infertility.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2020
Keywords
Non-neuronal cholinergic system, Choline acetyltransferase (ChAT), Proton-pump inhibitors (PPIs), Esomeprazole, Sperm motility, CASA tool, Enzyme kinetics, In silico analyses
National Category
Pharmacology and Toxicology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-430592 (URN)10.1016/j.bcp.2020.114212 (DOI)000594224300002 ()32866455 (PubMedID)
Funder
Swedish Research Council, 2016-01806The Dementia Association - The National Association for the Rights of the DementedThe Karolinska Institutet's Research FoundationMagnus Bergvall FoundationLars Hierta Memorial FoundationGun och Bertil Stohnes StiftelseTore Nilsons Stiftelse för medicinsk forskningStiftelsen Gamla Tjänarinnor
Available from: 2021-01-11 Created: 2021-01-11 Last updated: 2021-01-11Bibliographically approved
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