Investigating the Role of JAK/STAT as a Potential Pharmacological Target for Epilepsy Öffentlichkeit
Kapur, Anika (Spring 2025)
Abstract
Epilepsy is a prevalent neurological condition characterized by recurrent spontaneous seizures. The efficacy of current pharmacological agents used to treat epilepsy is limited. Hence, there is a need for the identification of new treatment approaches that incorporate diverse pharmacological targets. Daily administration of CP-690,550 (Tofacitinib Citrate), a JAK 3/1 competitive inhibitor, to kainite-induced epileptic mice in the chronic phase decreases seizure severity and frequency that persisted even after the medication was discontinued. In these same mice, epilepsy-associated deficits in spatial memory and working memory were also rescued. Single-nucleus RNA sequencing (RNAseq) from the same study determined that the general observed upregulation of inflammatory markers was driven by STAT3. A complete understanding of which pathways Tofacitinib is suppressing in which specific cell types to produce this anti-inflammatory effect remains unresolved. Here in this study, we first establish and optimize a model for LPS induction to mimic the inflammatory cellular environment in the epileptic brain. Subsequently, we use the model of LPS induction to probe the exact effects of Tofacitinib on inflammatory mediators in two relevant cells: BV2-hEP2 microglia and THP1 monocytes. Our hypothesis is that direct inhibition of the JAK/STAT pathway by CP-690,550 reduces the production of inflammatory mediators by microglia and monocytes. We find a promising trend in Tofacitinib’s suppression of LPS-induced IL-6 mRNA in BV2-hEP2 microglia but fail to detect any statistically significant effects of Tofacitinib on the mRNA levels of any of the screened pro-inflammatory markers within the selected dose range in THP1 monocytes.
Table of Contents
Table of Contents
Introduction………………………………………………………………………………………………2
Materials and Methods…………………………………………………………………………………22
Results……………………………………………………………………………………………………30
Discussion………………………………………………………………………………………………45
Conclusions and Future Directions…………………………………………………………52
Limitations…………………………………………………………………………….………………54
References………………………………………………………………………………….…………55
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