HMGB1 mediates inflammation response of epileptogenicity in tuberous sclerosis complex-related epilepsy.

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.