Browsing by Author "Mensah, J.A"

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    Antidepressant Effect And The Possible Mechanism(S) Of Action Of Secondary Metabolites From Trichilia Monadelpha In Murine Models
    (University of Ghana, 2016-07) Mensah, J.A
    Background: Current conventional antidepressant drugs have delayed onset of action, significant adverse effects, are costly and about 30-40% of patients are non-responsive, underscoring the need for alternative therapies for depression. Presently, no known scientific evidence exists to support the efficacy of Trichilia monadelpha in depression treatment, though used in Ghana in managing psychosis, epilepsy and mood disorders. Aim: This study investigated the antidepressant effect of secondary metabolites extracted from the stem bark of T. monadelpha and the possible mechanism(s) of action of the most efficacious metabolite in murine models of depression. Method: Powdered stem bark of T. monadelpha (4 kg) was sequentially extracted with petroleum ether, ethyl acetate and 70% (v/v) ethanol and the extracts screened for phytochemical constituents. A preliminary investigation using the Irwin test was conducted before the antidepressant effect of the three extracts were investigated using the forced swimming test (FST) and tail suspension test (TST). In a separate experiment, antidepressant effect of the extracted secondary metabolites [alkaloids (ALK), flavonoids (FLV), saponins (SAP), terpenoids (TER), tannins (TAN)] from the most efficacious extract was evaluated. Furthermore, the most efficacious metabolite was assessed for rapid-onset of antidepressant effect using the open space swim test and its mechanism(s) of action were investigated. Results: The LD50 of all the three extracts was above 3000 mg kg-1 in mice. All three extracts (30-300 mg kg-1 p.o) showed dose dependent antidepressant activity in both FST and TST (P< 0.001) with the hydroethanolic extract (HEE) showing the highest efficacy (Emax = 80.55). The FLV, ALK and SAP (dose for the metabolites: 30-300 mg kg-1 p.o) extracted from HEE showed significant antidepressant effect (P < 0.001) in the FST and TST with the ALK being the most efficacious (Emax = 76.40). The ALK (30-300 mg kg-1p.o) exhibited rapid-onset of antidepressant effect on day two of treatment and sustained it throughout the period of drug treatment in the open space swim test. Pre-treatment with para-chlorophenylalanine (a tryptophan hydroxylase inhibitor; 200 mg kg-1 i.p) reversed the antidepressant effect of the ALK (30-300 mg kg-1 p.o) and cyproheptadine (a 5-HT2 receptor antagonist; 80 mg kg-1, i.p) diminished its antidepressant effect, suggesting possible allosteric enhancement of serotoninergic activity. Similarly, pre-treatment with α- methyldopa (200 mg kg-1, i.p) and/or reserpine (1 mg kg-1 s.c) abolished the antidepressant effect of the ALK indicating enhancement of noradrenergic activity. Pre-treatment with yohimbine (a selective α2-receptor antagonist; 3 mg kg -1 , p.o) potentiated the antidepressant effect of the ALK, suggesting inhibitory effect on α2-receptors. Pre-treatment with prazosin (a selective α1- receptor antagonist; 3 mg kg-1 , p.o) failed to reverse the effect of the ALK. Pre-treatment with D- serine (glycine/NMDA receptor agonist; 600 mg kg -1 ,i.p) reversed the antidepressant effect of the ALK while D-cycloserine (glycine/NMDA receptor partial agonist) potentiated the anti-immobility effect of the ALK, suggesting inhibitory effect on glycine/NMDA receptor complex. Antidepressant effect of the ALK was attenuated by pretreatment with L-arginine (NOS substrate; 750 mg kg -1 , i.p), however, a synergistic effect was observed with the pre-treatment of L-NAME (a non-selective NOS inhibitor; 30 mg kg -1 ,i.p) and methylene blue (direct inhibitor of both NOS and sGC; 10 mg kg -1 ,i.p) implicating the involvement of L-arginine-NO-cGMP pathway. The ALK significantly increased curling score in TST suggestive of enhancement of opioidergic activity. Conclusion: The study showed that all three extracts had potent antidepressant activity. The ALK extracted from HEE exhibited a rapid and sustained antidepressant effect and may act via an interplay of noradrenergic, serotoninergic, glycine/NMDA receptor, L-arginine-NOcGMP nitric oxide and opioidergic pathways