Thrombin mediates seizures following cortical injury-induced status epilepticus

The neurobiological mechanisms underlying acute seizures, status epilepticus (SE), and cerebral edema following cortical insult are unknown. Currently, benzodiazepines are first-line therapy for SE, and mechanistic insight could lead to improved treatment for cortical-injury-related seizures. Cobalt was implanted in the supplementary motor cortex (M2). Homocysteine was administered sixteen hours later, which converted focal seizures to SE. Seizures were monitored by video-EEG. Blood-brain barrier (BBB) damage was assessed using Evans blue staining and Western blotting. Cerebral edema was evaluated using MRI and a wet-dry method of measuring brain water content. We also assessed if diazepam and thrombin inhibitor α-naphthylsulphonylglycyl-4-amidinophenylalanine piperidine (α-NAPAP) administered individually or together treated seizures and protected animals from edema and mortality. Blood proteins thrombin and albumin were present in the brain parenchyma, primarily in the ipsilateral hemisphere, of animals in SE. Evans blue staining revealed a wider spread of albumin in post-SE animals compared to those in early SE. The seizures rapidly became diazepam-resistant, and the drug did not reduce death due to cerebral edema. Thrombin inhibitor α-NAPAP reduced cerebral edema and prevented seizures. A combination of diazepam and α-NAPAP treatment suppressed seizures, lowered edema, and improved survival. Thrombin extravasation triggers seizures and edema following neocortical injury, and it is a therapeutic target. A combination of benzodiazepines and anti-thrombin agents could terminate SE and reduce mortality.