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

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-HTR2A/2C and 5-HTR3A/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-HTR2A/2C receptors may be implicated in the low anticonvulsant effect in CBWS.Communicated by Ramaswamy H. Sarma.

Anxiolytic-like effect of chalcone N-{(4'-[(E)-3-(4-fluorophenyl)-1-(phenyl) prop-2-en-1-one]} acetamide on adult zebrafish (Danio rerio): Involvement of the GABAergic system.

Benzodiazepines are the standard drugs for the treatment of anxiety, but their undesirable side effects make it necessary to develop new anxiolytic drugs. The objective of this study was to evaluate the possible anxiolytic-simile effect of synthetic chalcone N-{(4'-[(E)-3-(4-fluorophenyl)-1-(phenyl) prop-2-en-1-one]} acetamide (PAAPFBA) on adult zebrafish (Danio rerio). PAAPFBA was synthesized with an 88.21% yield and its chemical structure was determined by 1H and 13C NMR. Initially, animals (n = 6/group) were treated (4 or 12 or 40 mg/kg, intraperitoneal) with PAAPFBA and were submitted to acute toxicity and open field tests. Then, other groups (n = 6/each) received PAAPFBA for the analysis of its effect on the Light & Dark Test. The participation of the GABAergic system was also assessed using the GABAA antagonist flumazenil. Molecular docking was performed using the GABAA receptor. The effect of PAAPFBA on anxiety induced by alcohol withdrawal was analyzed. PAAPFBA was non-toxic, reduced the locomotor activity, and showed an anxiolytic-like effect in both models. This effect was reduced by pre-treatment with the flumazenil. In agreement with in vivo studies, molecular docking indicated an interaction between chalcone and the GABAA receptor. The results suggest that PAAPFBA is an anxiolytic agent mediated via the GABAergic system.