Tofacitinib overcomes first-line drug resistance in a pre-clinical model of epilepsy
- 1University of Wisconsin at Madison
Abstract
One-third of people with epilepsy continue to have seizures despite antiseizure medications (ASMs), and available therapies often fail to improve disabling cognitive comorbidities. Patients with drug resistant epilepsy report that the adverse effects of medications along with their comorbidities can have a greater negative impact on the quality of life than seizures. We previously identified recurrent JAK/STAT3 activation in chronic epilepsy and showed that transient treatment with the JAK inhibitor tofacitinib (CP690550) durably suppresses seizures and restores cognition in mice. Here, we tested CP690550 as an add-on therapy after failure of carbamazepine (CBZ), a common first line treatment for epilepsy, in a mouse model of multifocal temporal lobe epilepsy. In CBZ-resistant animals, dual therapy with CP690550 reduced median seizure frequency and time spent seizing by an order of magnitude; most dual therapy responders had no observed behavioral seizures during treatment. CP690550 also restored spatial working and short-term memory. We found that cognitive rescue was independent of seizure response. Our work suggests that JAK/STAT inhibition can overcome ASM nonresponse while independently improving epilepsy-associated cognitive dysfunction.
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BibTeX
@misc{koehler2026tofacitinib,
title = {{Tofacitinib overcomes first-line drug resistance in a pre-clinical model of epilepsy}},
author = {J. Koehler and O. R. Hoffman and Q. R. Harvey and B. A. Schoenike and J. E. C. Espina and A. Roopra},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.06.743311},
url = {https://www.biorxiv.org/content/10.64898/2026.08.06.743311v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Tofacitinib overcomes first-line drug resistance in a pre-clinical model of epilepsy
AU - J. Koehler
AU - O. R. Hoffman
AU - Q. R. Harvey
AU - B. A. Schoenike
AU - J. E. C. Espina
AU - A. Roopra
PY - 2026
DA - 2026/08/06
PB - bioRxiv
DO - 10.64898/2026.08.06.743311
UR - https://www.biorxiv.org/content/10.64898/2026.08.06.743311v2
AB - One-third of people with epilepsy continue to have seizures despite antiseizure medications (ASMs), and available therapies often fail to improve disabling cognitive comorbidities. Patients with drug resistant epilepsy report that the adverse effects of medications along with their comorbidities can have a greater negative impact on the quality of life than seizures. We previously identified recurrent JAK/STAT3 activation in chronic epilepsy and showed that transient treatment with the JAK inhibitor tofacitinib (CP690550) durably suppresses seizures and restores cognition in mice. Here, we tested CP690550 as an add-on therapy after failure of carbamazepine (CBZ), a common first line treatment for epilepsy, in a mouse model of multifocal temporal lobe epilepsy. In CBZ-resistant animals, dual therapy with CP690550 reduced median seizure frequency and time spent seizing by an order of magnitude; most dual therapy responders had no observed behavioral seizures during treatment. CP690550 also restored spatial working and short-term memory. We found that cognitive rescue was independent of seizure response. Our work suggests that JAK/STAT inhibition can overcome ASM nonresponse while independently improving epilepsy-associated cognitive dysfunction.
ER -