en فارماكوگنوزی و فارماسيوتيكس Pharmacognosy & Pharmaceutics پژوهشی Research <div style="text-align: justify;"><b><span style="font-size:10.0pt"><span new="" roman="" style="font-family:" times="">Background:</span></span></b><span style="font-size:10.0pt"><span new="" roman="" style="font-family:" times=""> Major depressive disorder affects more than 300 million people worldwide. <i>Citrus medica</i> L. essential oil (CMEO), rich in terpenes such as limonene, has shown antidepressant-like effects in preclinical models, potentially through hippocampal BDNF/CREB signaling, and may offer a safer natural alternative to conventional antidepressants. <b>Objective:</b> This study aimed to investigate the antidepressant-like effects of CMEO on depression-like behaviors induced by lipopolysaccharide (LPS) in mice and to elucidate potential underlying mechanisms involving hippocampal BDNF/p-CREB signaling and brain nitric oxide (NO) levels. <b>Methods:</b> CMEO composition was characterized by gas chromatography&ndash;mass spectrometry (GC-MS). Depression-like behavior was induced by intraperitoneal LPS injection (1 mg/kg). Mice were randomly assigned to four groups: Control, LPS, CMEO 50 mg/kg + LPS, and CMEO 100 mg/kg + LPS. Behavioral assessments included the Forced Swimming Test (FST), Tail Suspension Test (TST), and Open Field Test (OFT). Biochemical analyses measured hippocampal phosphorylated CREB (p-CREB) and brain-derived neurotrophic factor (BDNF), as well as brain NO levels. <b>Results:</b> GC-MS identified ten CMEO constituents, with limonene as the dominant compound (93.96%). CMEO at 50 and 100 mg/kg significantly reduced immobility time in the FST and TST versus the LPS group, indicating attenuated depressive-like behavior. CMEO also restored hippocampal BDNF and p-CREB levels and significantly reduced LPS-elevated NO. <b>Conclusion:</b> CMEO alleviates depression-like behaviors in an LPS-induced mouse model, potentially via upregulation of hippocampal BDNF and p-CREB and reduction of NO. The high limonene content may contribute to these effects, supporting CMEO as a promising natural candidate for managing depressive disorders.</span></span></div> Citrus medica, Lipopolysaccharide, Depression, cAMP response element-binding protein, Brain-Derived Neurotrophic Factor, Antidepressant-like effect 37 52 http://jmp.ir/browse.php?a_code=A-10-688-11&slc_lang=en&sid=1 Neda Kari-Khameneh neda.kari00@yahoo.com 100319475328460049436 0009-0007-2627-9942 No Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran Samira Shirooie shirooie@gmail.com 100319475328460049437 100319475328460049437 No Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran Mitra Tarlan mittn678@yahoo.com 100319475328460049438 100319475328460049438 No Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran Mohammad Hosein Farzaei mh.farzaei@gmail.com 100319475328460049439 100319475328460049439 Yes Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran