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Evidence of an antidepressant-like effect of xylopic acid mediated by serotonergic mechanisms

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Abstract

Background

Depression causes significant debilitating symptoms and economic burden. Current management is challenged by slow onset of action and modest efficacies of antidepressants; thus, the search for newer antidepressants remains relevant. We evaluated the antidepressant effects of a kaurene diterpene, xylopic acid (XA), in zebrafish and mouse models.

Methods

The chronic unpredictable stress (CUS) protocol in zebrafish and the tail suspension test (TST), forced swim test (FST), lipopolysaccharide-induced depression-like behaviour test (LID) and repeated open space swimming test (OSST) in mice were used. We further examined the impact of depleting monoamines on XA’s antidepressant effects. The contribution of glutamatergic and nitrergic pathways on the antidepressant effect of XA in mice and XA’s effects on 5-HT receptors and monoamine oxidase (MAO) enzymes were also evaluated. Finally, XA’s influence on neuroprotection was evaluated by measuring BDNF and oxidative stress enzymes in whole brain. XA doses (1–10 μM) in zebrafish and (10, 30, 100 mg kg−1) in mice exerted potent antidepressant-like potential in FST, TST, LID and showed fast-onset antidepressant-like property in the OSST.

Results

The antidepressant-like properties in mice were reversed by blocking synthesis/release of serotonin but not noradrenaline using p-chlorophenylalanine and α-methyl-p-tyrosine, respectively. This antidepressant-like effect was potentiated by d-cycloserine and Nω-Nitro-l-arginine methyl ester (l-NAME) but not by d-serine and L-arginine. XA also evoked partial agonist-like effects on 5-hydroxytrptamine receptors on the rat fundus but it did not have MAO inhibition effect. It also increased BDNF, glutathione and antioxidant enzymes.

Conclusion

Therefore, xylopic acid possesses antidepressant-like effects largely mediated by serotonergic and neuroprotective mechanisms.

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Acknowledgements

The authors are grateful to technicians of the Departments of Pharmacology in Kwame Nkrumah University of Science and Technology and in University of Cape Coast for their technical support at various stages of the project.

Funding

This work was funded using personal funds of all contributing authors.

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Authors and Affiliations

  1. Department of Pharmacology, School of Medical Sciences, University of Cape Coast, Cape Coast, Ghana

    Robert Peter Biney

  2. School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana

    Robert Peter Biney & Elvis Ofori Ameyaw

  3. Department of Pharmacology and Toxicology, School of Pharmacy, University of Health and Allied Sciences, Ho, Ghana

    Charles Kwaku Benneh, Donatus Wewura Adongo & Eric Woode

  4. Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

    Eric Woode

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  1. Robert Peter Biney
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Contributions

RPB conducted all experiments, analysed the data and wrote the first draft of manuscript. CKB participated in the carrying experiments on mechanism of action and zebrafish assays. DWA participated in chronic depression experiments and analyses of the data. EW and EOA conceptualised the work, provided supervision of the experiments and reviewed the analyses. All authors reviewed the final manuscript.

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Correspondence to Robert Peter Biney.

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Biney, R.P., Benneh, C.K., Adongo, D.W. et al. Evidence of an antidepressant-like effect of xylopic acid mediated by serotonergic mechanisms. Psychopharmacology 238, 2105–2120 (2021). https://doi.org/10.1007/s00213-021-05835-6

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