Antidepressant-Like Effects of Pithecellobium dulce Fruit Extract in a Chronic Unpredictable Stress-Induced Zebrafish Larvae Model: Behavioral, Molecular, and Phytochemical Insights.

Background Depression is a multifactorial neuropsychiatric disorder involving alterations in neuroplasticity, neurotransmission, and oxidative stress. Zebrafish larvae are a useful model for studying stress-induced behavioral changes. Pithecellobium dulce, rich in bioactive phytochemicals, has reported antioxidant properties, but its effects in stress models remain underexplored. Methods Zebrafish larvae were subjected to a chronic unpredictable stress (CUS) paradigm and divided into control, CUS, extract, CUS + standard (sertraline), and CUS + P. dulce extract (1 mg/mL) groups (n = 20). Behavioral assays included color preference, vertical exploration, thigmotaxis, and light-dark tests. Toxicity assessment, phytochemical screening, gas chromatography-mass spectrometry (GC-MS) analysis, DPPH antioxidant assay, and quantitative real-time PCR analysis of brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase-2 (TPH2) were performed. Results CUS induced significant behavioral deficits, including reduced exploration and increased dark preference. Pithecellobium dulce treatment improved these behaviors without observable toxicity at 1 mg/mL (no observed adverse effect concentration). Phytochemical analysis confirmed alkaloids, flavonoids, tannins, saponins, and phenolics. GC-MS identified bioactive compounds such as 5-hydroxymethylfurfural. The extract showed concentration-dependent antioxidant activity (max 84.83%; IC50 ~38 µg/mL). BDNF and TPH2 expression were reduced in CUS and showed partial restoration following treatment. Conclusions Pithecellobium dulce extract was associated with improvement in stress-induced behavioral alterations, potentially involving antioxidant effects and modulation of neuroplasticity and serotonergic pathways. However, findings are based on indirect evidence and require further mechanistic and translational validation.