Echinatin as a multimodal modulator of monoaminergic system: Preclinical evidence for antidepressant-like activity

Mounting evidence highlights flavonoids as multitarget candidates for central nervous system disorders because they can cross the blood-brain barrier and modulate diverse neurotransmitter pathways. Echinatin, a chalcone-type flavonoid from Glycyrrhiza species, has not previously been evaluated in behavioral models relevant to mood disorders. Here, we examined whether echinatin exerts antidepressant-like effects in validated rodent tests and explored the underlying monoaminergic mechanisms using pharmacological manipulations. Male BALB/c mice received echinatin (20 or 30 mg/kg), fluoxetine (10 mg/kg) or reboxetine (20 mg/kg). Antidepressant-like activity was assessed in the tail-suspension and modified forced-swimming tests, while motor performance was evaluated with the Rota-rod and the activity-meter. To delineate monoaminergic involvement, mice were pretreated with p-chlorophenylalanine (PCPA; serotonin synthesis inhibitor), α-methyl-p-tyrosine (AMPT; catecholamine synthesis inhibitor), WAY-100635 (serotonin 5-HT1A receptor antagonist), phentolamine (α-adrenoceptor antagonist), propranolol (β-adrenoceptor antagonist), SCH-23390 (dopamine D1 receptor antagonist), sulpiride (dopamine D2/D3 receptor antagonist) or ketanserin (serotonin 5-HT2A/5-HT2C receptor antagonist). Echinatin at 30 mg/kg markedly reduced immobility in both behavioral tests, producing effects comparable to reference antidepressants, without affecting locomotor activity or motor coordination. The anti-immobility effect was reversed by serotonergic (PCPA, WAY-100635), noradrenergic (AMPT, phentolamine, propranolol) and dopaminergic (SCH-23390, sulpiride) interventions, but was not altered by ketanserin. These findings provide the first pharmacological evidence that echinatin elicits antidepressant-like effects through broad monoaminergic modulation and support its further evaluation as a potential lead compound for antidepressant drug development.