Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

Benjamin Kirchweger; Luiz Carlos Klein-Junior; Dagmar  Pretsch; Ya Chen; Sylvian Cretton; André L.  Gasper; Yvan Vander Heyden; Philippe Christen; Johannes Kirchmair; Amélia T. Henriques; Judith M. Rollinger

doi:10.3389/fnins.2022.826289

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

Benjamin Kirchweger, Luiz Carlos Klein-Junior, Dagmar Pretsch, Ya Chen, Sylvian Cretton, André L. Gasper, Yvan Vander Heyden, Philippe Christen, Johannes Kirchmair, Amélia T. Henriques, Judith M. Rollinger

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Abstract

Nemorosine A (1) and fargesine (2), the main azepine-indole alkaloids of Psychotria nemorosa, were explored for their pharmacological profile on neurodegenerative disorders (NDs) applying a combined in silico–in vitro–in vivo approach. By using 1 and 2 as queries for similarity-based searches of the ChEMBL database, structurally related compounds were identified to modulate the 5-HT2A receptor; in vitro experiments confirmed an agonistic effect for 1 and 2 (24 and 36% at 10 μM, respectively), which might be linked to cognition-enhancing properties. This and the previously reported target profile of 1 and 2, which also includes BuChE and MAO-A inhibition, prompted the evaluation of these compounds in several Caenorhabditis elegans models linked to 5-HT modulation and proteotoxicity. On C. elegans transgenic strain CL4659, which expresses amyloid beta (Aβ) in muscle cells leading to a phenotypic paralysis, 1 and 2 reduced Aβ proteotoxicity by reducing the percentage of paralyzed worms to 51%. Treatment of the NL5901 strain, in which α-synuclein is yellow fluorescent protein (YFP)-tagged, with 1 and 2 (10 μM) significantly reduced the α-synuclein expression. Both alkaloids were further able to significantly extend the time of metallothionein induction, which is associated with reduced neurodegeneration of aged brain tissue. These results add to the multitarget profiles of 1 and 2 and corroborate their potential in the treatment of NDs.

Original language	English
Article number	826289
Number of pages	12
Journal	Frontiers in Neuroscience
Volume	16
DOIs	https://doi.org/10.3389/fnins.2022.826289
Publication status	Published - 14 Mar 2022

Bibliographical note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Keywords

bioactive natural products
molecular target prediction
alkaloids
Psychotria nemorosa
Caenorhabditis elegans
5-HT2A
neurodegeneration

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Kirchweger, Benjamin ; Klein-Junior, Luiz Carlos ; Pretsch, Dagmar ; Chen, Ya ; Cretton, Sylvian ; Gasper, André L. ; Vander Heyden, Yvan ; Christen, Philippe ; Kirchmair, Johannes ; Henriques, Amélia T. ; Rollinger, Judith M. / Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans. In: Frontiers in Neuroscience. 2022 ; Vol. 16.

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title = "Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans",

abstract = "Nemorosine A (1) and fargesine (2), the main azepine-indole alkaloids of Psychotria nemorosa, were explored for their pharmacological profile on neurodegenerative disorders (NDs) applying a combined in silico–in vitro–in vivo approach. By using 1 and 2 as queries for similarity-based searches of the ChEMBL database, structurally related compounds were identified to modulate the 5-HT2A receptor; in vitro experiments confirmed an agonistic effect for 1 and 2 (24 and 36{\%} at 10 μM, respectively), which might be linked to cognition-enhancing properties. This and the previously reported target profile of 1 and 2, which also includes BuChE and MAO-A inhibition, prompted the evaluation of these compounds in several Caenorhabditis elegans models linked to 5-HT modulation and proteotoxicity. On C. elegans transgenic strain CL4659, which expresses amyloid beta (Aβ) in muscle cells leading to a phenotypic paralysis, 1 and 2 reduced Aβ proteotoxicity by reducing the percentage of paralyzed worms to 51{\%}. Treatment of the NL5901 strain, in which α-synuclein is yellow fluorescent protein (YFP)-tagged, with 1 and 2 (10 μM) significantly reduced the α-synuclein expression. Both alkaloids were further able to significantly extend the time of metallothionein induction, which is associated with reduced neurodegeneration of aged brain tissue. These results add to the multitarget profiles of 1 and 2 and corroborate their potential in the treatment of NDs.",

keywords = "bioactive natural products, molecular target prediction, alkaloids, Psychotria nemorosa, Caenorhabditis elegans, 5-HT2A, neurodegeneration",

author = "Benjamin Kirchweger and Klein-Junior, {Luiz Carlos} and Dagmar Pretsch and Ya Chen and Sylvian Cretton and Gasper, {Andr{\'e} L.} and {Vander Heyden}, Yvan and Philippe Christen and Johannes Kirchmair and Henriques, {Am{\'e}lia T.} and Rollinger, {Judith M.}",

note = "All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.",

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Kirchweger, B, Klein-Junior, LC, Pretsch, D, Chen, Y, Cretton, S, Gasper, AL, Vander Heyden, Y, Christen, P, Kirchmair, J, Henriques, AT & Rollinger, JM 2022, 'Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans', Frontiers in Neuroscience, vol. 16, 826289. https://doi.org/10.3389/fnins.2022.826289

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans. / Kirchweger, Benjamin; Klein-Junior, Luiz Carlos; Pretsch, Dagmar ; Chen, Ya; Cretton, Sylvian; Gasper, André L. ; Vander Heyden, Yvan; Christen, Philippe; Kirchmair, Johannes; Henriques, Amélia T.; Rollinger, Judith M.

In: Frontiers in Neuroscience, Vol. 16, 826289, 14.03.2022.

Research output: Contribution to journal › Article

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AU - Kirchweger, Benjamin

AU - Klein-Junior, Luiz Carlos

AU - Pretsch, Dagmar

AU - Chen, Ya

AU - Cretton, Sylvian

AU - Gasper, André L.

AU - Vander Heyden, Yvan

AU - Christen, Philippe

AU - Kirchmair, Johannes

AU - Henriques, Amélia T.

AU - Rollinger, Judith M.

N1 - All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

PY - 2022/3/14

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N2 - Nemorosine A (1) and fargesine (2), the main azepine-indole alkaloids of Psychotria nemorosa, were explored for their pharmacological profile on neurodegenerative disorders (NDs) applying a combined in silico–in vitro–in vivo approach. By using 1 and 2 as queries for similarity-based searches of the ChEMBL database, structurally related compounds were identified to modulate the 5-HT2A receptor; in vitro experiments confirmed an agonistic effect for 1 and 2 (24 and 36% at 10 μM, respectively), which might be linked to cognition-enhancing properties. This and the previously reported target profile of 1 and 2, which also includes BuChE and MAO-A inhibition, prompted the evaluation of these compounds in several Caenorhabditis elegans models linked to 5-HT modulation and proteotoxicity. On C. elegans transgenic strain CL4659, which expresses amyloid beta (Aβ) in muscle cells leading to a phenotypic paralysis, 1 and 2 reduced Aβ proteotoxicity by reducing the percentage of paralyzed worms to 51%. Treatment of the NL5901 strain, in which α-synuclein is yellow fluorescent protein (YFP)-tagged, with 1 and 2 (10 μM) significantly reduced the α-synuclein expression. Both alkaloids were further able to significantly extend the time of metallothionein induction, which is associated with reduced neurodegeneration of aged brain tissue. These results add to the multitarget profiles of 1 and 2 and corroborate their potential in the treatment of NDs.

AB - Nemorosine A (1) and fargesine (2), the main azepine-indole alkaloids of Psychotria nemorosa, were explored for their pharmacological profile on neurodegenerative disorders (NDs) applying a combined in silico–in vitro–in vivo approach. By using 1 and 2 as queries for similarity-based searches of the ChEMBL database, structurally related compounds were identified to modulate the 5-HT2A receptor; in vitro experiments confirmed an agonistic effect for 1 and 2 (24 and 36% at 10 μM, respectively), which might be linked to cognition-enhancing properties. This and the previously reported target profile of 1 and 2, which also includes BuChE and MAO-A inhibition, prompted the evaluation of these compounds in several Caenorhabditis elegans models linked to 5-HT modulation and proteotoxicity. On C. elegans transgenic strain CL4659, which expresses amyloid beta (Aβ) in muscle cells leading to a phenotypic paralysis, 1 and 2 reduced Aβ proteotoxicity by reducing the percentage of paralyzed worms to 51%. Treatment of the NL5901 strain, in which α-synuclein is yellow fluorescent protein (YFP)-tagged, with 1 and 2 (10 μM) significantly reduced the α-synuclein expression. Both alkaloids were further able to significantly extend the time of metallothionein induction, which is associated with reduced neurodegeneration of aged brain tissue. These results add to the multitarget profiles of 1 and 2 and corroborate their potential in the treatment of NDs.

KW - bioactive natural products

KW - molecular target prediction

KW - alkaloids

KW - Psychotria nemorosa

KW - Caenorhabditis elegans

KW - 5-HT2A

KW - neurodegeneration

U2 - 10.3389/fnins.2022.826289

DO - 10.3389/fnins.2022.826289

M3 - Article

VL - 16

JO - Frontiers in Neuroscience

JF - Frontiers in Neuroscience

SN - 1662-4548

M1 - 826289

ER -

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

Abstract

Bibliographical note

Keywords

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