Chebulinic acid potentiates antidepressant-like properties through monoaminergic systems and adult hippocampal neurogenesis in laboratory mice

Abstract

Background: Chebulinic acid, an ellagitannin, present in the fruits of Terminalia chebula has been reported to show antioxidant, anti-nociceptive and antidepressant properties. Pre-clinical and clinical studies have suggested the involvement of monoamines, particularly the serotonergic and noradrenergic systems in the molecular mechanism of depression. Research has also suggested that the mode of action of antidepressants may be via hippocampal neurogenesis. There is no report elucidating how chebulinic acid potentiates its antidepressant properties. This study was therefore carried out to investigate its probable antidepressant mechanisms of action.

Methods: Involvement of serotonergic, cholinergic, dopaminergic and adrenergic systems were studied using Forced Swimming Test, Tail Suspension Test (as models of depression) and Open Field Test which measures ambulatory behaviours. Antagonists Prazosin, an alpha1-adrenergic receptor blocker (62.5 μg/kg, i.p.), metergoline, a 5HT2 receptor blocker (4 mg/kg, i.p.), atropine, a -muscarinic cholinergic receptor blocker (1 mg/kg i.p.) and sulpiride, a dopaminergic3 receptor blocker (50 mg/kg i.p) were administered before chebulinic acid (20 mg/kg). Animals were also treated with chebulinic acid for 7, 21 and 28 days to see the effect of continuous administration, after which neuronal cell proliferation in the hippocampus was determined by Immunohistochemistry using Ki-67 antibody.

Results: Results showed that mobility was reversed in animals pre-treated with metergoline significantly (p < 0.05), but not sulpiride, prazosin and atropine, showing a possible involvement of serotoninergic system. There is a marked increase in the number of proliferating neuronal cells as observed after chronic treatment with chebulinic acid.

Conclusion: Chebulinic acid probably exhibits its antidepressant-like activity via serotonergic systems. The presence of proliferating cells in the chronic-treated groups indicates antidepressant-like activities, which is consistent with the time course for the therapeutic action of antidepressants. Chebulinic acid may serve as a template in the development of an alternative antidepressant drug.

Keywords: Terminalia chebula, hippocampus, antidepressant-like activities, serotonergic systems.

Résumé
Contexte: L’acide chebulinique, une ellagitannine, présent dans les fruits de Terminalia chebula, a révélé des propriétés neurologiques anti oxydantes, anti-nociceptif et antidépresseur. Des études précliniques et cliniques ont suggéré l’implication de monoamines, en particulier les systèmes séroto-nergiques et noradrénergiques dans le mécanisme moléculaire de la dépression. La recherche a également suggéré que le mode d’action des antidépresseurs peut se faire à travers la neurogenèse de l’hippocampe. Il n’existe aucun rapport expliquant comment l’acide chebulinique potentialise ses propriétés antidépresseur. Cette étude a donc été réalisée pour étudier son (ses) mécanisme (s) d’action antidépresseur (s) probable (s).

Méthodes: l’implication des systèmes sérotonergiques, cholinergiques, dopaminergiques et adrénergiques a été étudiée en utilisant le test de natation forcée, le test de suspension de la queue (en tant que modèles de dépression) et le test de terrain ouvert qui mesure les comportements ambulatoires. Les antagonistes Prazosin, un bloqueur des récepteurs alpha1-adrénergiques (62,5 μg / kg, ip), la métérergine, un bloqueur de récepteur 5HT2 (4 mg / kg, ip), l’atropine, un inhibiteur de récepteur cholinergique a -muscarinique (1 mg / kg ip) et le sulpiride, un bloqueur de récepteur D2 et D3 (50 mg / kg ip) a été administré avant l’acide chebulinique (20 mg / kg). Les animaux ont également été traités avec de l’acide chebulinique pendant 7, 21 et 28 jours pour voir l’effet de l’administration continue, après quoi la prolifération des cellules neuronales dans l’hippocampe a été déterminée par l’immunohistochimie en utilisant l’anticorps Ki-67.

Résultats: Les résultats ont montré que la mobilité a été inversée chez les animaux prétraités avec de la méthergoline de manière significative (p  0,05), mais pas le sulpiride, la prazosine et l’atropine, ce qui montre une implication possible du système sérotoninergique. Il y a une augmentation marquée du nombre de cellules neuronales proliférantes observées après un traitement chronique avec de l’acide chebulinique.

Conclusion: l’acide chebulinique présente probablement son fonctionnement antidépresseur par des systèmes sérotonergiques. La présence de cellules proliférantes dans les groupes traités par voie chronique indique des activités semblables aux antidépresseurs, ce qui correspond au cours de l’action thérapeutique des antidépresseurs. L’acide chebulinique peut servir de modèle dans le développement d’un autre médicament antidépresseur.

Mots-clés: Terminalia chebula, hippocampe, activités antidépresseurs, systèmes sérotonergiques.

Correspondence: Dr. S.A. Onasanwo, Department of Physiology, College of Medicine, University of Ibadan, Ibadan, Nigeria. Email: samphil2002@yahoo.com, sa.onasanwo@gmail.ui.edu.ng

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