Title: A consortium data science approach reveals a potent, seizure suppressing and memory restoring target for drug resistant epilepsy.

Abstract: All current drug treatments for epilepsy, a neurological disorder affecting more than 50 million people, merely treat symptoms, and a third of patients with epilepsy do not respond to medication. There are no disease-modifying treatments that may be administered briefly to patients to enduringly eliminate spontaneous seizures and reverse cognitive deficits. Applying network approaches to transcriptomic data collected from a mouse model of drug resistant epilepsy and human temporal lobectomy samples, we confirm a rapid and transient induction of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway within days of epileptogenic insult.  We have discovered that this is followed by a resurgent reignition of the JAK/STAT pathway weeks to months later with the onset of spontaneous seizures. Targeting the first wave of JAK/STAT activation after epileptic insult does not prevent disease. However, brief inhibition of the second wave with CP690550 (tofacitinib) enduringly suppresses seizures, rescues deficits in spatial memory, and alleviates epilepsy-associated histopathological alterations. Seizure suppression lasts for months after the final dose. These results indicate that reignition of inflammatory JAK/STAT3 signaling in chronic epilepsy opens a window for disease modification with tofacitinib.

Aix-Marseille Université
INS - Faculté de Médecine, 27, Boulevard Jean Moulin
Marseille, 13005, France

Amphi 3