Single nucleus sequencing of mouse hippocampi four days after pilocarpine induced status epilepticus

All current drug treatments for epilepsy, a neurological disorder
affecting over 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-nuclei
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 transducers and activators
of transcription (JAK/STAT) pathway within days of epileptogenic insult.
This was followed by a resurgent activation 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
FDA-approved, orally available drug CP690550.