Kuang Suhui, Liu Tinghong, Yuan Liu, Xu Jinshan, Wang Yangshuo, Chen Feng, Liang Shuli
Functional Neurosurgery Department, National Children's Health Center of China, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China.
Sci Prog. 2025 Apr-Jun;108(2):368504251338653. doi: 10.1177/00368504251338653. Epub 2025 Jun 12.
ObjectiveEpileptogenic tubers (ETs) contribute to the epileptogenesis in patients with tuberous sclerosis complex (TSC). High mobility group protein B-1 (HMGB1) triggers inflammatory responses that impact neuronal electrical activity. We aimed to study the role of HMGB1 in epileptogenicity in TSC-related epilepsy.MethodsThis study included both human and animal models. ETs were identified through comprehensive preoperative evaluations and postoperative seizure outcomes following tuberectomy. Immunofluorescence was performed to assess the positive area and fluorescence intensity of HMGB1 and IL-1β in ETs and non-ETs. TSC2-GFAP-CKO mice and epileptic models were established. Mice in the prevention group (postnatal day 14) received daily injections of monoclonal HMGB1 or IL-1β antibodies for 22 days. Mice in the intervention group (postnatal day 28) received identical treatments. Genetic and proteomic analyses of HMGB1 and IL-1β were conducted on both TSC patients and animal models.ResultsHMGB1 and IL-1β were significantly overexpressed in ETs compared to non-ETs. HMGB1 was predominantly nuclear in non-ETs but mainly cytoplasmic in ETs. In animal models, HMGB1 and IL-1β expression at both the gene and protein levels was significantly upregulated in the TSC2-deficient group compared to the wild-type group. IL-1β expression was lower in the HMGB1-intervention group than in the model control group. Seizure frequency was reduced in both HMGB1 and IL-1β prevention and intervention groups compared to the model control.ConclusionsThe interference of HMGB1 and IL-1β significantly reduced the frequency of seizure attacks in TSC. Epileptic seizures serve as key triggers for HMGB1 translocation and subsequent release into the cytoplasm, contributing to seizure recurrence.
目的
致痫性结节（ETs）在结节性硬化症（TSC）患者的癫痫发生过程中起作用。高迁移率族蛋白B-1（HMGB1）引发炎症反应，影响神经元电活动。我们旨在研究HMGB1在TSC相关癫痫的致痫性中的作用。
方法
本研究包括人类和动物模型。通过术前综合评估和结节切除术后的癫痫发作结果来识别ETs。进行免疫荧光以评估ETs和非ETs中HMGB1和IL-1β的阳性面积和荧光强度。建立TSC2-GFAP-CKO小鼠和癫痫模型。预防组（出生后第14天）的小鼠每天注射单克隆HMGB1或IL-1β抗体，持续22天。干预组（出生后第28天）的小鼠接受相同的治疗。对TSC患者和动物模型进行HMGB1和IL-1β的基因和蛋白质组分析。
结果
与非ETs相比，ETs中HMGB1和IL-1β显著过表达。在非ETs中，HMGB1主要位于细胞核内，但在ETs中主要位于细胞质中。在动物模型中，与野生型组相比，TSC2缺陷组中HMGB1和IL-1β在基因和蛋白质水平的表达均显著上调。HMGB1干预组中的IL-1β表达低于模型对照组。与模型对照组相比，HMGB1和IL-1β预防组及干预组的癫痫发作频率均降低。
结论
HMGB1和IL-1β的干扰显著降低了TSC中的癫痫发作频率。癫痫发作是HMGB1易位并随后释放到细胞质中的关键触发因素，导致癫痫复发。
