Nelumbo nucifera Petals Ameliorate Depressive-like Symptom and Cognitive Deficit in Unpredictable Chronic Mild Stress Mouse Model

<b>Background</b> Chronic stress exposure has been widely recognized as a significant contributor to numerous central nervous system (CNS) disorders, leading to debilitating behavioral changes such as anxiety, depression, and cognitive impairments. The prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress disrupts the neuroendocrine balance and has detrimental effects on neuronal function and survival. <i>Nelumbo nucifera</i> (<i>N. nucifera</i>) Gaertn., commonly known as the lotus flower, is a traditional medicinal plant consumed for its purported benefits on mental and physical well-being. Despite its traditional use, limited scientific evidence supports these claims. <b>Methods</b> The present study explores the effects of <i>N. nucifera</i>, commonly known as the lotus flower, on cognitive performance and stress resilience in a mouse model subjected to unpredictable chronic mild stress (UCMS). <b>Results</b> Daily treatment significantly improved cognitive performance, alleviated depressive-like behaviors, and normalized hypothalamic-pituitary-adrenal (HPA) axis activity, as indicated by a 60.97% reduction in serum corticosterone. At the molecular level, <i>N. nucifera</i> petals also downregulated serum- and glucocorticoid-inducible kinase 1 (SGK1) mRNA expression while upregulating brain-derived neurotrophic factor (BDNF) mRNA expression and cyclic-adenosine monophosphate (cAMP) responsive element-binding protein (CREB) mRNA expression in the hippocampus and frontal cortex. These normalizations are critical, as chronic stress dysregulates HPA axis function, exacerbating behavioral changes. Furthermore, a phytochemical analysis resulted in the isolation of five major compounds, kaempferol (<b>1</b>), trifolin (<b>2</b>), kaempferol-3-neohesperidoside (<b>3</b>), icariside D₂ (<b>4</b>), and β-sitosterol (<b>5</b>), each demonstrating significant monoamine oxidase (MAO) inhibitory activity. <b>Conclusions</b> These compelling findings suggest that <i>N. nucifera</i> petals not only alleviate stress-induced mood and cognitive deficits but also offer a promising avenue for modulating the HPA axis and promoting neuroprotection via essential neurotrophic factors and enzymatic pathways. We advocate for its potential as a complementary and alternative medicine for effective stress management. Future investigations should further explore its mechanisms of action and evaluate its clinical applicability in stress-related disorders.