Ruxolitinib-dependent reduction of seizure load and duration is accompanied by spatial memory improvement in the rat pilocarpine model of temporal lobe epilepsy.

Abstract

Molecules with optimized pharmacokinetic properties selectively aimed at the inhibition of STAT3 phosphorylation in brain have recently emerged as potential disease modifying therapies for epilepsy. In the current study, pharmacological inhibition of JAK1/2 with the orally available, FDA-approved drug ruxolitinib, produced nearly complete inhibition of hippocampal STAT3 phosphorylation, and reduced the expression of its downstream target Cyclin D1, when administered to rats 30 ​min and 3 ​h after onset of pilocarpine-induced status epilepticus (SE). This effect was accompanied by significantly shorter seizure duration and lower overall seizure frequency throughout the 4 weeks of EEG recording, but did not completely prevent the development of epilepsy in ruxolitinib-treated male rats. Compared to DMSO-treated animals, administration of ruxolitinib also improved memory (Y maze) but did not impact motor function (open field) following SE. Taken together with our previous findings, the results of this study provide further evidence that inhibition of the JAK/STAT pathway may be a promising disease modifying strategy to reduce severity of acquired epilepsy after brain injury, but also point to the need to better understand and optimize inhibitors of this pathway.