Ursolic acid ameliorates stress and reactive oxygen species in C. elegans knockout mutants by the dopamine Dop1 and Dop3 receptors.

6533b824fe1ef96bd1280198

RESEARCH PRODUCT

Ursolic acid ameliorates stress and reactive oxygen species in C. elegans knockout mutants by the dopamine Dop1 and Dop3 receptors.

subject

Antioxidant medicine.medical_treatment Dopamine Longevity Pharmaceutical Science Pharmacology Neuroprotection Antioxidants 03 medical and health sciences chemistry.chemical_compound Gene Knockout Techniques 0302 clinical medicine Dopamine Stress Physiological Drug Discovery medicine Animals Humans Receptor Caenorhabditis elegans Caenorhabditis elegans Proteins 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences Reactive oxygen species Chemistry Receptors Dopamine D2 Receptors Dopamine D1 Receptors Dopamine D3 Triterpenes Molecular Docking Simulation Complementary and alternative medicine Dopamine receptor 030220 oncology & carcinogenesis Mutation Molecular Medicine Serotonin Trolox Reactive Oxygen Species medicine.drug Signal Transduction

description

Abstract Background Depression and stress-related disorders are leading causes of death worldwide. Standard treatments elevating serotonin or noradrenaline levels are not sufficiently effective and cause adverse side effects. A connection between dopamine pathways and stress-related disorders has been suggested. Compounds derived from herbal medicine could be a promising alternative. We examined the neuroprotective effects of ursolic acid (UA) by focusing on dopamine signalling. Methods Trolox equivalent capacity assay was used to determine the antioxidant activities of UA in vitro. C. elegans N2 wildtype and dopamine receptor-knockout mutants (dop-1-deficient RB665 and dop-3-deficient LX703 strains) were used as in vivo models. H2DCFDA and acute juglone assays were applied to determine the antioxidant activity in dependency of dopamine pathways in vivo. Stress was assessed by heat and acute osmotic stress assays. The influence of UA on overall survival was analyzed by a life span assay. The dop-1 and dop-3 mRNA expression was determined by real time RT-PCR. We also examined the binding affinity of UA towards C. elegans Dop1 and Dop3 receptors as well as human dopamine receptors D1 and D3 by molecular docking. Results Antioxidant activity assays showed that UA exerts strong antioxidant activity. UA increased resistance towards oxidative, osmotic and heat stress. Additionally, UA increased life span of nematodes. Moreover, dop-1 and dop-3 gene expression was significantly enhanced upon UA treatment. Docking analysis revealed stronger binding affinity of UA to C. elegans and human dopamine receptors than the natural ligand, dopamine. Binding to Dop1 was stronger than to Dop3. Conclusion UA reduced stress-dependent ROS generation and acted through Dop1 and to a lesser extent through Dop3 to reduce stress and prolong life span in C. elegans. These results indicate that UA could be a promising lead compound for the development of new antidepressant medications.

year	journal	country	edition	language
2020-10-04	Phytomedicine : international journal of phytotherapy and phytopharmacology

10.1016/j.phymed.2020.153439 https://pubmed.ncbi.nlm.nih.gov/33352493