# Fyn Mediated Neuroinflammatory Signaling in Epileptogenesis and Epilepsy

> **NIH NIH R21** · IOWA STATE UNIVERSITY · 2020 · $406,966

## Abstract

Project Summary/Abstract
Epilepsy is the third most common neurological disorder of humans worldwide and its lifetime prevalence is
~2% (>65 million people). About 10% of Americans experience a seizure during their lifetime and ~3% of them
develop epilepsy by the time they are 80 years of age. In the US, epilepsy management costs $15.5 billion/
year. About 1/3 of patients do not respond to any AEDs. The majority of the AEDs that do not cure epilepsy
are ion-channel targeted drugs. This suggests the need for development of drugs that target alternative
pathways to cure epilepsy. This is a major unmet clinical obligation due to poor understanding of the
mechanisms of epileptogenesis. Neuroinflammation is emerging as a mechanistic target for drug development
for temporal lobe epilepsy (TLE), the most common type of epilepsy associated with cognitive impairment.
Recently, we demonstrated the upregulation of Src family kinase Fyn, PKCδ, and gp91phox in the hippocampus
during epileptogenesis in the mouse and rat kainate (KA) models of TLE. The PKCδ activates NADPH oxidase
(NOX2) by phosphorylating the cytosolic p47phox subunit, which forms a functional NOX2 complex with the
membrane-associated gp91phox. This drives the production of ROS/RNS and activates NF-kB in microglia to
initiate neuroinflammation, which is known to reduce seizure threshold. Therefore, our overarching hypothesis
is that Fyn, the upstream of PKCδ-NOX2-NFkB signaling pathway, is a potential therapeutic target for
epileptogenesis/epilepsy. We propose to test the hypothesis in a rat model of TLE. KA-induced status
epilepticus (SE) in rat causes epilepsy (spontaneous, recurrent seizures (SRS)) through a well-characterized
process of neuroinflammation, nitro-oxidative stress, and neurodegeneration (“the disease promoters”). We will
characterize the time-course activation of the Fyn-PKCδ-NOX2 pathway components in microglia during
epileptogenesis (Aim 1), and validate the role of Fyn kinase in epileptogenesis by utilizing microglia-specific
rAAV-fyn-shRNA, and a novel Fyn/Src kinase inhibitor, saracatinib (SAR/AZD0530), in a rat model of TLE
(Aim 2). SAR is blood-brain barrier permeable and has excellent bioavailability in the brain at a low dose. Its
clinical tolerability and oral bioavailability has been demonstrated in phase IIa clinical trials for Alzheimer's
disease, breast cancer and bone cancer patients. In our preliminary studies, SAR significantly reduced SE
severity, SRS episodes, and prevented epileptogenesis (in >50% of the rats) in experimental models. We will
determine antiepileptogenic effects of rAAV- fyn-shRNA and SAR (also anti-epileptic effects) in real-time by
employing continuous video-EEG telemetry for 3 months, and the Morris water maze test to assess cognition
in both male and female rat KA model of TLE. We will measure cytokines, ROS, and RNS from the serum and
CSF, and the other disease promoters and the Fyn-PKCδ-NOX2 components in different cell types (microgli...

## Key facts

- **NIH application ID:** 9964030
- **Project number:** 1R21NS112779-01A1
- **Recipient organization:** IOWA STATE UNIVERSITY
- **Principal Investigator:** Thimmasettappa Thippeswamy
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,966
- **Award type:** 1
- **Project period:** 2020-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964030

## Citation

> US National Institutes of Health, RePORTER application 9964030, Fyn Mediated Neuroinflammatory Signaling in Epileptogenesis and Epilepsy (1R21NS112779-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9964030. Licensed CC0.

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