BACKGROUND: Radiation-induced cognitive dysfunction (RICD) is a prevalent and long-term complication of cranial radiotherapy, characterized by hippocampal-dependent learning and memory impairment that severely compromises quality of life in cancer survivors. Accumulating evidence implicates sustained mitochondrial damage and oxidative stress as central drivers of RICD pathogenesis; however, clinically effective disease-modifying interventions remain lacking.
PURPOSE: This study investigated the neuroprotective efficacy and molecular mechanisms of Senkyunolide I (SI), a bioactive phthalide derived from Ligusticum chuanxiong, in experimental models of RICD, with particular emphasis on mitochondrial quality control and antioxidant signaling.
METHODS: RICD was modeled using fractionated head-neck irradiation (7 × 3 Gy) in mice and X-ray-irradiated PC12 cells. Behavioral and cognitive performance was assessed using open field, novel object recognition, Y-maze, and Morris water maze paradigms. Longitudinal monitoring of body weight and intake behavior was conducted to characterize irradiation-associated physiological alterations. The systemic pharmacokinetic profile and hippocampal distribution of SI following oral administration were quantified by LC-MS/MS. Mechanistic analyses included biochemical assays of oxidative and inflammatory markers, immunofluorescence evaluation of glial activation, assessment of mitochondrial membrane potential and mitochondrial ROS, ultrastructural examination by transmission electron microscopy, and Western blot analysis of proteins involved in mitophagy, antioxidant defense, and apoptosis.
RESULTS: Oral SI administration markedly improved radiation-induced cognitive and behavioral impairments and exhibited rapid systemic absorption with enhanced hippocampal accumulation following irradiation. SI significantly attenuated oxidative stress and neuroinflammatory responses in hippocampal tissue, accompanied by preservation of mitochondrial structure and function. Mechanistically, SI restored PINK1-Parkin-mediated mitophagic flux and activated the KEAP1-Nrf2 antioxidant pathway. Pharmacological inhibition of autophagy and genetic silencing of PINK1 abolished SI-induced mitochondrial protection and antioxidant activation, confirming mitophagy as an essential upstream mechanism underlying SI-mediated neuroprotection.
CONCLUSION: Senkyunolide I effectively mitigates radiation-induced cognitive dysfunction by coordinating mitochondrial quality control and endogenous antioxidant defenses. These findings highlight the therapeutic potential of orally administered SI and support targeting mitochondrial homeostasis as a viable strategy for the treatment of RICD.
