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Induction of stress resistance and extension of lifespan in Chaenorhabditis elegans serotonin-receptor knockout strains by withanolide A.
Naß, Janine; Abdelfatah, Sara; Efferth, Thomas.
  • Naß J; Department of Pharmaceutical Biology, Institute of Biochemistry and Pharmacy, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
  • Abdelfatah S; Department of Pharmaceutical Biology, Institute of Biochemistry and Pharmacy, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
  • Efferth T; Department of Pharmaceutical Biology, Institute of Biochemistry and Pharmacy, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
Phytomedicine ; 84: 153482, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1051912
Semantic information from SemMedBD (by NLM)
1. Depressive disorder PROCESS_OF Persons
Subject
Depressive disorder
Predicate
PROCESS_OF
Object
Persons
2. Wild Type PART_OF Caenorhabditis elegans
Subject
Wild Type
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PART_OF
Object
Caenorhabditis elegans
3. serotonin receptor LOCATION_OF mRNA Expression
Subject
serotonin receptor
Predicate
LOCATION_OF
Object
mRNA Expression
4. fluoxetine AFFECTS Survival time
Subject
fluoxetine
Predicate
AFFECTS
Object
Survival time
5. serotonin receptor COEXISTS_WITH Wild Type
Subject
serotonin receptor
Predicate
COEXISTS_WITH
Object
Wild Type
6. Membrane Transport Proteins COEXISTS_WITH Wild Type
Subject
Membrane Transport Proteins
Predicate
COEXISTS_WITH
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Wild Type
7. serotonin receptor PART_OF Homo sapiens
Subject
serotonin receptor
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PART_OF
Object
Homo sapiens
8. Depressive disorder PROCESS_OF Persons
Subject
Depressive disorder
Predicate
PROCESS_OF
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Persons
9. Wild Type PART_OF Caenorhabditis elegans
Subject
Wild Type
Predicate
PART_OF
Object
Caenorhabditis elegans
10. serotonin receptor LOCATION_OF mRNA Expression
Subject
serotonin receptor
Predicate
LOCATION_OF
Object
mRNA Expression
11. fluoxetine AFFECTS Survival time
Subject
fluoxetine
Predicate
AFFECTS
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Survival time
12. serotonin receptor COEXISTS_WITH Wild Type
Subject
serotonin receptor
Predicate
COEXISTS_WITH
Object
Wild Type
13. Membrane Transport Proteins COEXISTS_WITH Wild Type
Subject
Membrane Transport Proteins
Predicate
COEXISTS_WITH
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Wild Type
14. serotonin receptor PART_OF Homo sapiens
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serotonin receptor
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PART_OF
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Homo sapiens
ABSTRACT

INTRODUCTION:

Approximately 300 million people worldwide suffer from depression. The COVID-19 crisis may dramatically increase these numbers. Severe side effects and resistance development limit the use of standard antidepressants. The steroidal lactone withanolide A (WA) from Withania somnifera may be a promising alternative. Caenorhabditis elegans was used as model to explore WA's anti-depressive and anti-stress potential.

METHODS:

C. elegans wildtype (N2) and deficient strains (AQ866, DA1814, DA2100, DA2109 and MT9772) were used to assess oxidative, osmotic or heat stress as measured by generation of reactive oxygen species (ROS), determination of lifespan, and mRNA expression of serotonin receptor (ser-1, ser-4, ser-7) and serotonin transporter genes (mod-5). The protective effect of WA was compared to fluoxetine as clinically established antidepressant. Additionally, WA's effect on lifespan was determined. Furthermore, the binding affinities and pKi values of WA, fluoxetine and serotonin as natural ligand to Ser-1, Ser-4, Ser-7, Mod-5 and their human orthologues proteins were calculated by molecular docking.

RESULTS:

Baseline oxidative stress was higher in deficient than wildtype worms. WA and fluoxetine reduced ROS levels in all strains except MT9772. WA and fluoxetine prolonged survival times in wildtype and mutants under osmotic stress. WA but not fluoxetine increased lifespan of all heat-stressed C. elegans strains except DA2100. Furthermore, WA but not fluoxetine extended lifespan in all non-stressed C. elegans strains. WA also induced mRNA expression of serotonin receptors and transporters in wildtype and mutants. WA bound with higher affinity and lower pKi values to all C. elegans and human serotonin receptors and transporters than serotonin, indicating that WA may competitively displaced serotonin from the binding pockets of these proteins.

CONCLUSION:

WA reduced stress and increased lifespan by ROS scavenging and interference with the serotonin system. Hence, WA may serve as promising candidate to treat depression.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Receptors, Serotonin / Caenorhabditis elegans / Caenorhabditis elegans Proteins / Withanolides / Longevity Limits: Animals Language: English Journal: Phytomedicine Journal subject: Complementary Therapies Year: 2021 Document Type: Article Affiliation country: J.phymed.2021.153482

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Receptors, Serotonin / Caenorhabditis elegans / Caenorhabditis elegans Proteins / Withanolides / Longevity Limits: Animals Language: English Journal: Phytomedicine Journal subject: Complementary Therapies Year: 2021 Document Type: Article Affiliation country: J.phymed.2021.153482