Mechanistic insights into the role of hesperidin and naringenin in experimental model of chronic unpredictable mild stress induced depression

Abstract

Depression resulting from chronic unpredictable mild stress (CUMS) is a growing global newlinehealth issue, linked to disruptions in the hypothalamic-pituitary-adrenal (HPA) axis, newlineelevated cortisol, and imbalances in key neurotransmitters like serotonin and dopamine. newlineThese changes contribute to heightened oxidative stress, neuroinflammation, and neuronal newlinedamage. This study explores the antidepressant-like effects of natural flavonoids newlineHesperidin (HSP) and Naringenin (NRG) known for their antioxidant, antiinflammatory, newlineand neuroprotective properties, and their ability to cross the blood-brain newlinebarrier. The research aimed to elucidate the molecular mechanisms underlying the newlinetherapeutic effects of HSP and NRG in a murine model of CUMS-induced depression, newlinefocusing on the 5-HT2A receptor, PI3K/Akt signaling, and TGF-and#946; pathway due to their newlineroles in neuroplasticity and inflammation. Male Swiss albino mice were subjected to 21- newlineday CUMS exposure and treated with HSP (100 and 200 mg/kg; p.o) or NRG (25 and 50 newlinemg/kg; p.o). Behavioral tests (FST, SPT, OFT), biochemical assays (corticosterone, newlinemonoamines, oxidative stress, and inflammatory markers), histological analysis of the newlineprefrontal cortex, and pharmacological interventions with pathway-specific modulators newlineDOI, 5HT2A agonist (5 mg/kg; s.c), LY294002, PI3K inhibitor (10 mg/kg; i.p) and newlineGW788388, TGF-and#946; inhibitor (3 mg/kg; p.o) were performed. Molecular docking and newlinedynamic simulations confirmed strong binding affinities of HSP and NRG to the target newlinereceptors. Both compounds significantly reversed behavioral deficits, normalized newlinebiochemical parameters, reduced neuroinflammation, oxidative damage, and preserved newlineneuronal structure. The reversal of benefits by pathway inhibitors confirmed the newlinemechanistic role of 5-HT2A, PI3K/Akt, and TGF-and#946; pathways. These findings suggest HSP newlineand NRG as promising, multitargeted phytopharmacological agents for managing stressrelated newlinedepression. newline