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

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

doi:10.3389/fnins.2022.826289

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.

Highlights

Indian tribes from Amazonia have been using leaves from Psychotria viridis for the preparation of Ayahuasca, a decoction applied in rituals for the treatment of various health problems, including mental diseases (Katchborian-Neto et al, 2020)
To identify the putative targets of 1 and 2, the alkaloids of interest were compared with a large set of compounds with measured bioactivities for a total of 4,600 proteins
We further evaluated the effect of these alkaloids on C. elegans transgenic strain NL5901 endowed with yellow fluorescent protein (YFP)-tagged α-synuclein (Figure 5B)

Summary

Introduction

Indian tribes from Amazonia have been using leaves from Psychotria viridis (in combination with Banisteriopsis caapi) for the preparation of Ayahuasca, a decoction applied in rituals for the treatment of various health problems, including mental diseases (Katchborian-Neto et al, 2020). Applied medicines include cholinesterase inhibitors, e.g., donepezil, galantamine, and rivastigmine, the N-methyl-D-aspartate-receptor-antagonist memantine, and Ginkgo biloba extract EGb 761 (Liu et al, 2015; Sharma et al, 2019; Nowak et al, 2021). None of these therapeutics is able to alleviate the causative disorder, but only delay the progression of symptoms related to AD. Several dopaminergic therapies are used as symptomatic treatment, e.g., levodopa (dopamine precursor), selegiline (monoamine oxidase B inhibitor), entacapone (catechol O-methyltransferase inhibitor), and pramipexole (dopamine agonist) (Poewe et al, 2017; Ntetsika et al, 2021)

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Conclusion