Antidepressant and Cognitive-Enhancing Effects of Stewartia pseudocamellia Maxim. Leaves in Chronic Unpredictable Mild Stress-Induced Mice Through HPA Axis Regulation and the BDNF/TrkB Pathway

<b>Background/Objectives</b>: <i>Stewartia pseudocamellia</i> Maxim. (<i>S. pseudocamellia</i>) has been reported to possess antioxidant and anti-inflammatory properties and contains various bioactive flavonoids and phenolic compounds. These components may contribute to neuroprotective effects relevant to depression and cognitive dysfunction. This study was conducted to evaluate the effects of 20% ethanolic extract from <i>S. pseudocamellia</i> leaves (ESP) on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and cognitive dysfunction in C57BL/6 mice. <b>Methods</b>: C57BL/6 mice were divided into six groups: normal control (NC), normal sample (NS; ESP 100 mg/kg), CUMS, L-theanine (Thea; 4 mg/kg), ESP 50 mg/kg, and ESP 100 mg/kg groups. Phytochemical profiling of ESP was performed using ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Depressive-like behaviors and cognitive function were assessed, along with stress-related hormonal regulation and associated cellular signaling pathways. <b>Results</b>: Phytochemical profiling of ESP identified procyanidin B2, epicatechin, rutin, catechin gallate, kaempferol 3-O-glucoside, and quercitrin as major constituents. ESP significantly alleviated CUMS-induced depressive-like behaviors and improved spatial learning and memory. These effects were associated with modulation of stress-related hormones in serum and hypothalamic-pituitary-adrenal (HPA) axis-related proteins in the brain. ESP also enhanced antioxidant defense by activating the Nrf2 signaling pathway and improving mitochondrial function. Furthermore, ESP attenuated neuroinflammation and apoptosis by regulating the TLR4/NF-κB and JNK pathways, and promoted neuroplasticity by modulating cholinergic activity, with enhanced BDNF/TrkB signaling in the cerebral cortex and hippocampus. <b>Conclusions</b>: Collectively, these findings suggest that ESP exerts protective effects against CUMS-induced depressive-like behaviors and cognitive deficits in a preclinical model.