基于活血通络理论和Gch1/BH4/eNOS通路探讨放射性认知障碍的发生机制及归辛颗粒的干预作用

放射性认知障碍是头颈放疗后常见的并发症，其发病机制尚不明确且缺乏有效防治药物。我们研究发现，电离辐射会造成脑血流低灌注的病理学特征，这与中医气滞血瘀的病机理论相符。Gch1/BH4/eNOS通路是维持血管舒张，保持血流灌注的重要通路。我们研究发现，电离辐射会降低患者血清BH4和小鼠脑基底动脉中Gch1水平，这提示该通络的改变在放射性认知障碍的发生中可能扮演重要作用。我院自研制剂归辛颗粒具有活血通络的中医作用，临床发现其可以改善放疗后血瘀型头痛患者的认知功能，但机制不明。我们发现归辛颗粒入脑成分含量最高的藁本内酯与Gch1具有高亲和力和催化活性，推测其通过Gch1/BH4/eNOS通路发挥干预作用。本研究拟分别从动物、组织、细胞层面，采用电生理、行为学、基因编辑等手段，明确放射性认知障碍新的发生机制及归辛颗粒的干预作用，为放射性认知障碍防治提供新靶点和增加归辛颗粒临床适应证用药提供基础理论。

Radiation cognitive impairment is a common complication after head and neck radiotherapy. Its pathogenesis is still unclear and there is a lack of effective prevention and treatment drugs. Our study found that ionizing radiation could cause the pathological characteristics of cerebral blood flow hypoperfusion, which was consistent with the pathogenesis theory of Qi stagnation and blood stasis in traditional Chinese medicine. Gch1/BH4/eNOS pathway is an important pathway to maintain vascular relaxation and maintain blood perfusion. In our study, we found that ionizing radiation reduced serum BH4 in patients and the Gch1 level in the basilar artery of mice, which suggests that this change in communication may play an important role in the development of radiation cognitive impairment. Guixin Keli, a self-made preparation in our hospital, has the effect of activating blood and dredging collaterals in traditional Chinese medicine. It has been clinically found to improve the cognitive function of patients with blood stasis type headache after radiotherapy, but the mechanism is unclear. We found that ligustilide, which had the highest content of brain components in Guixin Keli, had high affinity and catalytic activity with Gch1, and we speculated that it might play an intervention role through the Gch1/BH4/eNOS pathway. In this study, the new mechanism of radiation cognitive impairment and the intervention effect of Guixin Keli were clarified at the animal, tissue, and cell levels by using electrophysiology, behavior, gene editing, and other means, to provide a new target for the prevention and treatment of radiation cognitive impairment and the basic theory for increasing the clinical indications of Guixin Keli.