Abstracts

Rationale: Many brain insults including traumatic brain injury, stroke and status epilepticus (SE) cause the later development of epilepsy. However, there are currently no treatments that reduce epileptogenesis following brain injuries. Recent data shows that inhibiting the JAK/STAT pathway with the compound WP1066 at the time of brain insult attenuates the severity of the ensuing epilepsy. Specifically, rats given WP1066 at the time of pilocarpine-induced SE show a significant reduction in the frequency of spontaneous seizures compared to vehicle-injected animals up to 4 weeks following SE. However, unfavorable pharmacokinetic (PK) properties of WP1066 limit its potential for preclinical development. WP1066 is rapidly cleared from blood and brain and only transiently reduces activation of the JAK/STAT pathway. Methods: We have recently initiated PK studies on newly synthesized compounds and commercially available JAK/STAT inhibitors aimed at increasing the efficacy of JAK/STAT inhibition in brain following peripheral administration in rats. Drugs were administered at the onset of SE and animals were sacrificed at various time points following SE. Expression of phosphorylated STAT3 (pSTAT3) was measured via Western blot analysis.Results: One leading synthesized compound shows increased stability, improved blood-brain barrier penetration, and greater inhibition of pSTAT3 in both cultured hippocampal neurons and in brain following pilocarpine-induced SE in vivo. In our preliminary studies, this novel compound caused an ~200-fold increase in plasma and cortex concentrations compared to WP1066 1 hour after SE. In addition, Western blot analysis on rat hippocampi 1 hour after SE showed a ~45% reduction in pSTAT3 levels in rats injected with the new compound. The commercial inhibitors also showed higher in vivo plasma and cortex concentrations compared to WP1066 with one of them reducing pSTAT3 expression by 81% compared to controls (p = 0.026).Conclusions: These findings suggest that novel JAK/STAT inhibitors may have promise as disease modifying agents with potential to reduce development and/or severity of epilepsy following brain insults.