Antidepressant effect of Centella asiatica (L.) Urb. extract on reserpine-induced depression-like zebrafish [Danio rerio (F. Hamilton, 1822)] model via ¹H NMR metabolomics approach

The World Health Organization (WHO) recorded approximately 350 millions people around the world have sufferred or is sufferring from mental health disorders, such as depression, anxiety, schizophrenia and addictive behaviors. Current antidepressants have associated problems related to their use, such as prolonged delays in symptom resolution, low rates of full remissions, substantial residual symptoms post-treatment and high rates of relapse. Use of rodents as translational animal model have several limitations such as high costs, low throughput and time-consuming among others. The zebrafish is a new promising model in drug discovery research. Thus, objective of this study is to determine the behavioral effects and metabolites changes after exposure of C. asiatica extract (RECA) on the established zebrafish model of reserpine-induced depression. The antidepressant effect of marker triterpenoid saponins of C. asiatica were also evaluated via behavioural analysis. Depression was successfully induced in the zebrafish model by single intraperitoneal injection of 80 mg/kg BW which produced significant increase (F(3,32) = 46.71, p<0.0001) and decrease {t(9.25) = -5.772, p<0.0001} in freezing duration and reduced total distance travelled, respectively. A significant increase {t(11) = 0.0001} in cortisol level (6 fold increment) further supported the results. Treating the depression model with 150 mg/L of RECA via immersion technique, gave positive improvement in that the model showed significant reduction in freezing durations {t(16)= 3.302, p=0.005) and increase in total distance travelled {t(9)=1.646, p=0.046}. Similarly, the social interaction test (SIT) significantly increase {t(11)= 7.778, p=0.0001} contact duration of the zebrafishes. 1H NMR-based metabolomics analysis of the zebrafish brain extract showed twelve metabolites, i.e lactate, β-hydroxyisovaleric acid, glutamine, choline, histidine, glutamate, histamine, valine, histidine, L-fucose, betaine, and GABA were significantly reduced in the depression model. Treatment with RECA was able to significantly increase the levels of six metabolites i.e L-fucose, lactate, betaine, valine, β-hydroxyisovaleric acid, and ethanolamine, back towards normal levels, consistent with moderate of the depressed condition. The current study revealed that C. asiatica has antidepressant properties and further investigation should be carried out towards obtaining a better insight into the pathology of depression and mechanism of C. asiatica as antidepressant.

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