Protective Effects of Agastache rugose Against Cyclophosphamide-Induced Cognitive Impairment in Mice: Experimental Validation and Compound-Target Prediction

Background: The chemotherapeutic and immunosuppressive agent cyclophosphamide (CYP), which is widely used in cancer treatment, can cause oxidative damage and inflammation in the brain, resulting in behavioral abnormalities, including cognitive impairment. Agastache rugosa (AR) has been traditionally used to treat digestive disorders and it has several physiological activities. Methods and Results: We investigated the neuroprotective effects of an AR ethanol extract against CYP-induced neurodegeneration and cognitive dysfunction. Free radical scavenging assays confirmed the antioxidant activity of the AR extract. C57BL/6 mice were orally administered an AR extract (100 or 200 mg/kg) for seven days, followed by an intraperitoneal injection of CYP (50 mg/kg). Mice exhibited memory impairment in a contextual fear conditioning test 24 h after CYP treatment. However, AR pretreatment notably improved behavioral deficits. Histological analysis demonstrated that CYP administration reduced the immunoreactivity of Ki67 (a proliferative cell marker) and doublecortin (an immature progenitor cell marker) in the dentate gyrus of the hippocampus, whereas AR pretreatment considerably normalized the levels of these markers. Subsequently, network pharmacology was used to investigate the potential genes involved in the ameliorative action of AR on CYP-induced neurodegeneration and memory impairment, which suggested BCL2, JUN, and MAPK3 as key candidates. Conclusions: These findings demonstrate that AR pretreatment protects against CYP-induced neurodegeneration and cognitive impairment. In addition, network pharmacology analysis suggests that AR compounds may provide neuroprotection against CYP-induced neuroinflammation by modulating key target genes such as BCL2, JUN, and MAPK3.