Neohesperidin from <i>Aurantii Fructus Immaturus</i> Exerts Antidepressant-Like Effects and Modulates Glucocorticoid Receptor Signaling in a Chronic Stress Model

Depression, a mood disorder characterized by persistent negative emotions and impaired functioning, is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptor (GR) dysfunction. <i>Aurantii Fructus Immaturus</i> (AFI), the immature fruit of <i>Citrus aurantium</i> Linné, has been used in East Asian herbal medicine, and neohesperidin (NHD), a principal constituent of AFI, has been studied for its antidepressant properties. This study aimed to elucidate the mechanisms underlying the antidepressant effects of NHD, focusing on its ability to enhance GR expression and activity, thereby normalizing HPA axis function and mitigating neuroinflammation. AFI extract and its component NHD ameliorated depression-like behaviors in chronic restraint stress mice with normalized plasma corticosterone (CORT) levels. Moreover, NHD treatment reduced hippocampal expression of proinflammatory cytokine genes (<i>TNFA</i>, <i>IL6</i>, <i>IL1A</i>, and <i>IL1B</i>) while enhancing GR expression, particularly the <i>NR3C1</i> exon 1₇ and 1₁₀ variants homologous to human GR variants implicated in depression. In cultured cells, NHD not only reversed CORT-induced neurite atrophy in N2a cells but also suppressed lipopolysaccharide-induced cytokine release in BV2 microglia. Notably, gene silencing of the GR via siRNA abrogated these neuritogenic and antineuroinflammatory effects, demonstrating that NHD exerts its antidepressant and neuroinflammation-suppressive actions in a GR-dependent manner. These findings suggest a promising therapeutic potential for AFI and NHD in stress-related depressive disorders, offering a multi-target approach that addresses both stress response and neuroinflammation through modulation of GR expression.