# Cofilin Signaling in Hemorrhagic Stroke

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2020 · $386,250

## Abstract

Hemorrhagic stroke constitutes only 10-15% of total stroke types but is responsible for higher mortality
rates and survivors suffer from severe disabilities and post-stroke cognitive impairments (PSCI). Except
for surgical intervention, there is no effective treatment for intracerebral hemorrhage (ICH). In order to
develop effective treatment modalities, it is imperative to gain a better understanding of the pathways
that are active after ICH, in particular, during secondary injury involving microglial activation mediated
neuroinflammation and PSCI. Microglia play an important role responding to injuries in the brain and a
comprehensive understanding of the microglia-specific signaling during episodes of injury are pivotal for
mitigating the damage induced by ICH. The three cofilin isoforms: actin binding protein, cofilin1 (cofilin)
and cofilin2 are important regulators of F-actin turnover and reorganization and alterations in these
processes can lead to neurodegenerative diseases. Cofilin rods/aggregates formed during pathological
conditions play a crucial role in microglial activation, synaptic dysfunction and neuronal death. As a
mechanistic proof of concept, targeting cofilin with siRNA or inhibitor in mice led to decreased
hematoma volume, improved neurobehavioral functions and PSCI after experimental ICH.
Immunofluorescence analysis of human autopsy ICH brain specimens also showed widespread cofilin
activation in microglia in the perihematoma area. The novel findings support the scientific premise that
cofilin signaling plays a key role in the secondary phase of ICH involving microglial activation and
inflammation and subsequent PSCI and led us to hypothesize that inhibition of cofilin presents a novel
therapeutic strategy. The proposed hypothesis will be addressed in three aims. Aim 1 will identify cofilin
rods/aggregates and microglial activation in human ICH autopsy brain specimens by performing
immunofluorescence. The spatiotemporal pattern of cofilin rods/aggregates and PSCI will be determined
in wildtype (WT) mice over a protracted period of 60 days following ICH. Aim 2 will identify whether
microglial or neuronal cofilin is mediating neuroinflammation and PSCI after ICH by using neuron and
microglia-specific cofilin knockout mice. Aim 3 will study the therapeutic potential of a novel first of its
class, cofilin inhibitor in aged WT mice subjected to ICH. The studies outlined in this proposal will
provide insights on the role of cofilin signaling in ICH induced-microglial activation, inflammation and
PSCI and the identification of potential therapeutic agents for drug discovery and development.

## Key facts

- **NIH application ID:** 10051992
- **Project number:** 1R01NS112642-01A1
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** Zahoor Ahmad Shah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,250
- **Award type:** 1
- **Project period:** 2020-06-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051992

## Citation

> US National Institutes of Health, RePORTER application 10051992, Cofilin Signaling in Hemorrhagic Stroke (1R01NS112642-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10051992. Licensed CC0.

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