Authors: Olivia R. Hoffman, Jennifer L. Koehler, Jose Ezekiel Clemente Espina, Anna M. Patterson, Emily S. Gohar, Emanuel M. Coleman, Barry A. Schoenike, Claudia Espinosa-Garcia, Felipe Paredes, Nicholas H. Varvel, Raymond J. Dingledine, Jamie L. Maguire, Avtar S. Roopra
Published: 2025-03-19
DOI: 10.1126/scitranslmed.adt0527
Source: Full article
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 whole tissue and single-nucleus transcriptomic data collected from mouse models of temporal lobe epilepsy and publicly available transcriptomic data from human temporal lobectomy samples, we confirmed a previously described pattern of rapid and transient induction of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway within days of epileptogenic insult. This was followed by a resurgent activation 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 did not prevent seizures. However, inhibition of the second wave with CP690550 (tofacitinib) over a 2-week period enduringly suppressed seizures, rescued deficits in spatial memory, and alleviated epilepsy-associated histopathological alterations. Seizure suppression lasted for at least 2 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 the US Food and Drug Administration–approved, orally available drug CP690550.