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Assessments of Ceanothanes Triterpenes as Cholinesterase Inhibitors: An Investigation of Potential Agents with Novel Inspiration for Drug Treatment of Neurodegenerative Diseases.

ABSTRACT: The purpose of this study was to determine the inhibitory capacity of ceanothanes triterpenes isolate from Chilean Rhamnaceae on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Seven ceanothanes triterpenes were isolated from aerial parts of plant material by classical phytochemical methods or prepared by the hemisynthetic method. Structures were determined by the spectroscopic method (¹H-NMR and ¹³C NMR) and mass spectrometry (MS). AChE and BChE activity were determined by the Ellmann method for all compounds. All tested compounds exerted a greater affinity to AChE than to BChE, where compound 3 has an IC₅₀ of 0.126 uM for AChE and of >500 uM to BChE. Kinetic studies indicated that its inhibition was competitive and reversible. According to the molecular coupling and displacement studies of the propidium iodide test, the inhibitory effect of compound 3 would be produced by interaction with the peripheral anionic site (PAS) of AChE. The compounds tested (1-7) showed an important inhibitory activity of AChE, binding to PAS. Therefore, inhibitors that bind to PAS would prevent the formation of the AChE-Aβ complex, constituting a new alternative in the treatment of Alzheimer's disease (AD).

SUBMITTER: Munoz-Nunez E

PROVIDER: S-EPMC9318782 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Assessments of Ceanothanes Triterpenes as Cholinesterase Inhibitors: An Investigation of Potential Agents with Novel Inspiration for Drug Treatment of Neurodegenerative Diseases.

Muñoz-Nuñez Evelyn E Quiroz-Carreño Soledad S Pastene-Navarrete Edgar E Seigler David S DS Céspedes-Acuña Carlos C Martínez Valenzuela Ignacio I Oppliger Muñoz Martina M Salas-Burgos Alexis A Alarcón-Enos Julio J

Metabolites 20220720 7

The purpose of this study was to determine the inhibitory capacity of ceanothanes triterpenes isolate from Chilean Rhamnaceae on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Seven ceanothanes triterpenes were isolated from aerial parts of plant material by classical phytochemical methods or prepared by the hemisynthetic method. Structures were determined by the spectroscopic method (1H-NMR and 13C NMR) and mass spectrometry (MS). AChE and BChE activity were determined by ...[more]

PMID: 35888792

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Project description:IntroductionmiRNAs are small noncoding elements known to regulate different molecular processes, including developmental and executive functions in the brain. Dysregulation of miRNAs could contribute to brain neurodegeneration, as suggested by miRNA profiling studies of individuals suffering from neurodegenerative brain diseases (NBDs). Here, we report rare miRNA variants in patients with Alzheimer's dementia (AD) and frontotemporal dementia (FTD).MethodsWe initially used whole exome sequencing data in a subset of FTD patients (n = 209) from Flanders-Belgium. We then performed targeted resequencing of variant-harboring miRNAs in an additional subset of FTD patients (n = 126) and control individuals (n = 426). Lastly, we sequenced the MIR885 locus in a Flanders-Belgian AD cohort (n = 947) and a total number of n = 755 controls.ResultsWES identified rare seed variants in MIR656, MIR423, MIR122 and MIR885 in FTD patients. Most of these miRNAs bind to FTD-associated genes, implicated in different biological pathways. Additionally, some miRNA variants create novel binding sites for genes associated with FTD. Sequencing of the MIR885 locus in the AD cohort initially showed a significant enrichment of MIR885 variants in AD patients compared to controls (SKAT-O, p-value = 0.026). Genetic association was not maintained when we included sex and APOE status as covariates. Using the miRVaS prediction tool, variants rs897551430 and rs993255773 appeared to evoke significant structural changes in the primary miRNA. These variants are also predicted to strongly downregulate mature miR885 levels, in line with what is reported for MIR885 in the context of AD.DiscussionFunctional investigation of miRNAs/variants described in this study could propose novel miRNA-mediated molecular cascades in FTD and AD pathogenicity. Furthermore, we believe that the genetic evidence presented here suggests a role for MIR885 in molecular mechanisms involved in AD and warrants genetic follow-up in larger cohorts to explore this hypothesis.

Dataset Information

Assessments of Ceanothanes Triterpenes as Cholinesterase Inhibitors: An Investigation of Potential Agents with Novel Inspiration for Drug Treatment of Neurodegenerative Diseases.

Publications

Assessments of Ceanothanes Triterpenes as Cholinesterase Inhibitors: An Investigation of Potential Agents with Novel Inspiration for Drug Treatment of Neurodegenerative Diseases.

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