Investigating the Role of JAK/STAT as a Potential Pharmacological Target for Epilepsy 公开

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

About this Honors Thesis

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
关键词	Epilepsy CP-690,550 (Tofacitinib) JAK/STAT Neuroinflammation
Committee Chair / Thesis Advisor	Nicholas Varvel, Emory University
Committee Members	Richard Himes, Emory University Tracy McGill, Emory University

最新修改

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	Investigating the Role of JAK/STAT as a Potential Pharmacological Target for Epilepsy ()	2025-04-22 16:31:29 -0400	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions