Phytoconstituents of Indian mustard honey impart antidepressant activity in reserpine-induced depressed condition through activation of TrkB/CREB/BDNF pathway in hippocampus

Depression is a global health issue, with traditional antidepressants raising safety concerns. Indian mustard honey (MH) offers a potential alternative due to its health benefits, though its antidepressant effects remain unexplored. This study investigates the neuroprotective and antidepressant effects of MH in HT-22 cells in vitro and in Wistar rats in vivo. Chemical constituents of MH were identified using liquid chromatography-mass spectrometry (LC-MS). Effects of MH on phosphorylated tyrosine kinase receptor B (p-TrkB), brain-derived neurotropic factor (BDNF) and phosphorylated cyclic AMP-dependent response element-binding protein (p-CREB) were assessed in reserpine-treated HT-22 cells and rat models. Antidepressant effects in rats were evaluated using forced swim, tail suspension and locomotor activity tests, along with hippocampal histopathology and molecular analyses. MH profiling identified key polyphenols with antioxidant properties. In HT-22 cells, MH showed neuroprotection at 60 mg/mL (p < 0.001), and upregulated p-TrkB, BDNF, and p-CREB (p < 0.001) against reserpine-induced oxidative stress. In rats, compared to fluoxetine, MH at 1 g/kg BW increased locomotor activity by ∼2.3 fold and reduced immobility by ∼50% and 25% in the tail suspension and forced swim tests (p < 0.001), respectively, showing comparable/ better antidepressant effects. It also preserved hippocampal architecture and upregulated p-TrkB, BDNF, and p-CREB (p < 0.001) levels compared to reserpine-treated rats. MH demonstrated antioxidant, neuroprotective and antidepressant activities in in vitro and in vivo models, suggesting therapeutic potential. However, further studies on additional pathways, including β-catenin/Wnt, MAPK/ERK, along with pharmacokinetics, are essential before recommending MH as an antidepressant agent.