Antidepressant Effect And The Possible Mechanism(S) Of Action Of Secondary Metabolites From Trichilia Monadelpha In Murine Models

ABSTRACT

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-1

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p.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.