Senkyunolide I rescues radiation-induced cognitive deficits by restoring synaptic plasticity

Radiation-induced cognitive deficits (RICD) are a major complication after radiotherapy and are linked to disrupted synaptic plasticity, oxidative stress, and neuroinflammation. This study aimed to determine whether senkyunolide I (SI) can prevent or reverse RICD and to delineate associated mechanistic pathways. Adult male C57BL/6 mice underwent fractionated cranial irradiation (3 Gy/day for 7 days) and received SI intraperitoneally at 30 or 120 mg/kg. We assessed behavioural performance, hippocampal synaptic function, neuronal integrity, and redox/inflammatory biomarkers. SI attenuated radiation-related metabolic and locomotor disturbances and improved cognition, evidenced by higher Morris water maze probe performance (target-quadrant time, P < 0.001) and increased novel object recognition discrimination (1 h and 24 h, P < 0.05). Electrophysiology showed partial restoration of hippocampal LTP, accompanied by reversal of NR1/NR2A/NR2B downregulation. Nissl staining indicated preserved neuronal density. Biochemically, SI increased SOD and GSH-Px activities (P < 0.01) and reduced MDA (P < 0.001), while suppressing TNF-α and IL-6 (P < 0.001) and restoring BDNF (P < 0.05). In sum, SI mitigated RICD via coordinated antioxidant, anti-inflammatory, neurotrophic, and synaptic mechanisms.These preclinical results warrant further validation in clinical studies to determine pharmacokinetics, brain penetration, dose translation, and long-term safety.