: To explore the potential pathogenic mechanism of high mobility group box 1 (HMGB1) to epileptogenesis of focal cortical dysplasia (FCD) and its role as a novel therapeutic target.

FCD is a neurodevelopmental disease characterized by drug-resistant epilepsy. There is no effective pharmacological intervention targeting at its epileptogenic process. HMGB1, a chromatin binding protein released by necrotic cells following biological stress, was found to have a high expression in surgical specimens resected from FCD patients. However, the role of HMGB1 in epileptogenesis in FCD and its potential of becoming a therapeutic target remain unknown.

We measured the expression levels of HMGB1 in both surgical specimens resected from FCD patients and dysplastic cortical tissues from FCD rats (prenatal freeze lesion model).  Seizure severity of FCD rats were evaluated after administration of exogenous HMGB1 (1μg) or anti-HMGB1 antibodies (at the dose of 1mg/kg and 3mg/kg) in both juvenile (Postnatal Day 16, P16) and adult rats (P50). Locomotion and cognitive functions were also assessed in rats given antibodies at P16.

We found an increased expression of HMGB1, mainly from neurons and astrocytes, in both FCD surgical specimens and FCD rats at P50. HMGB1 also exhibited a high expression in FCD rats at P16, yet mostly from microglia. Intracerebral injection of HMGB1 at P16 and P50 both attenuated the seizure severity and shortened the latency to generalized seizures (Racine stage >= 4). A single dose of monoclonal antibodies against HMGB1, when given at P16 rather than at P50, significantly alleviated seizures (both seizure stage and latency to generalized seizures) in FCD rats in a dose-dependent manner. Locomotion and cognitive functions also improved after administration of monoclonal antibodies at P16.

HMGB1 provides a potential effective therapy to halt the development and progression of epilepsy in FCD.