Diterpene Sonderianin isolated from Croton blanchetianus exhibits acetylcholinesterase inhibitory action and anxiolytic effect in adult zebrafish (Danio rerio) by 5-HT system

Abstract

Croton blanchetianus is known as ‘marmeleiro preto’, a very widespread shrub in Northeast Brazil. Terpenoids, steroids and phenolic compounds are among the reported secondary metabolites of the Croton genus that are a potential source of bioactive compounds. This study evaluated the anxiolytic potential of clerodine-type diterpene, sonderianin (CBWS) isolated from the stem bark of C. blanchetianus and its mechanism of action in adult zebrafish (Danio rerio) (ZFa). The anticonvulsant and anti-acetylcholinesterase effects have also been explored. ZFa (n = 6/group) were treated intraperitoneally (ip; 20 µL) with CBWS (4, 12 and 40 mg/kg) and vehicle (3% DMSO; 20 µL) and subjected to locomotor activity tests, as well as toxicity acute 96 h. CBWS was also administered for analysis in the light/dark test. The involvement of the serotonergic system (5-HT) was investigated using 5-HTR₁, 5-HTR_2A/2C and 5-HTR_3A/3B receptor antagonists. Anxiolytic doses were tested for pentylenetetrazol-induced seizure in ZFa. The inhibitory activity of the enzyme acetylcholinesterase (AChE) was measured. CBWS was not considered toxic and reduced locomotor activity. The results of the present study identified for the first time the interaction of the diterpene sonderianina in the CNS. This study provides evidence that CBWS has an anxiolytic effect mediated by serotonergic (5-HT) involvement and anti-acetylcholinesterase action. The 5-HTR₁ and 5-HTR_2A/2C receptors may be implicated in the low anticonvulsant effect in CBWS.

Communicated by Ramaswamy H. Sarma

Keywords:

• Diterpene
• anxiety
• 5-HT
• zebrafish
• Croton

Acknowledgements

The authors thank FUNCAP (Research Support Foundation of the State of Ceará), CAPES (Coordination for the Improvement of Higher Education Personnel) and CNPq (National Council for Scientific and Technological Development) for the financial support and scholarship. Northeastern Center for the Application and Use of Nuclear Magnetic Resonance (CENAUREMN).

Disclosure statement

All the authors declare that they have no competing interests.

Ethics approval and consent to participate

The experimental protocols were approved by the Ethics Committee on the Use of Animals at the State University of Ceará (CEUA-UECE). This article does not contain any studies with human participants

Consent for publication

Not applicable.

Authors contributions

Conceptualization, Hélcio Silva dos Santos and Maria K.A. Ferreira; methodology, Joyce dos R. Lima and Antônio W. da Silva; validation, Emanuelle Machado Marinho; and Jane E.S.A. de Menezes^a formal analysis, Ketelly V. B. Sales; resources, Alexandre Magno R. Teixeira and Francisco Ernani A. Magalhães; writing—original draft preparation; writing—review and editing Paulo N. Bandeira and Matheus Nunes da Rocha; supervision, Emmanuel Silva Marinho and Márcia Machado Marinho. All authors have read and agreed to the published version of the manuscript

Availability of supporting data

All the data generated and discussed during this work are included in this published article and in the supplementary information file.

Additional information

Funding

Hélcio Silva dos Santos acknowledges financial support from the PQ-BPI/FUNCAP (Grant#: BP4-0172-00075.01.00/20).