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Updated: Jun 28, 2026
Acute Brain Trauma in Mice Followed By Longitudinal Two-photon Imaging
Published on: April 6, 2014
Cofilin Inhibitor Protects against Traumatic Brain Injury-Induced Oxidative Stress and Neuroinflammation
Ghaith A Bahader1, Antonisamy William James1, Daniyah A Almarghalani2
1Department of Medicinal and Biological Chemistry, The University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614, USA.
Abstract:
Microglial activation and failure of the antioxidant defense mechanisms are major hallmarks in different brain injuries, particularly traumatic brain injury (TBI). Cofilin is a cytoskeleton-associated protein involved in actin binding and severing. In our previous studies, we identified the putative role of cofilin in mediating microglial activation and apoptosis in ischemic and hemorrhagic conditions. Others have highlighted the involvement of cofilin in ROS production and the resultant neuronal death; however, more studies are needed to delineate the role of cofilin in oxidative stress conditions. The present study aims to investigate the cellular and molecular effects of cofilin in TBI using both in vitro and in vivo models as well as the first-in-class small-molecule cofilin inhibitor (CI). An in vitro H2O2-induced oxidative stress model was used in two different types of cells, human neuroblastoma (SH-SY5Y) and microglia (HMC3), along with an in vivo controlled cortical impact model of TBI. Our results show that treatment with H2O2 increases the expression of cofilin and slingshot-1 (SSH-1), an upstream regulator of cofilin, in microglial cells, which was significantly reduced in the CI-treated group. Cofilin inhibition significantly attenuated H2O2-induced microglial activation by reducing the release of proinflammatory mediators. Furthermore, we demonstrate that CI protects against H2O2-induced ROS accumulation and neuronal cytotoxicity, activates the AKT signaling pathway by increasing its phosphorylation, and modulates mitochondrial-related apoptogenic factors. The expression of NF-E2-related factor 2 (Nrf2) and its associated antioxidant enzymes were also increased in CI-treated SY-SY5Y. In the mice model of TBI, CI significantly activated the Nrf2 and reduced the expression of oxidative/nitrosative stress markers at the protein and gene levels. Together, our data suggest that cofilin inhibition provides a neuroprotective effect in in vitro and in vivo TBI mice models by inhibiting oxidative stress and inflammatory responses, the pivotal mechanisms involved in TBI-induced brain damage.
Insights
Cofilin inhibition protects brain cells from damage after traumatic brain injury (TBI). This study shows cofilin inhibition reduces oxidative stress and inflammation, offering a potential new treatment for TBI.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Microglial activation and impaired antioxidant defenses are key in brain injuries like TBI.
- Cofilin, a cytoskeleton protein, is implicated in microglial activation, apoptosis, and oxidative stress.
Purpose of the Study:
- To investigate cofilin's role in TBI-induced oxidative stress and neuroinflammation.
- To evaluate the neuroprotective effects of a novel cofilin inhibitor (CI) in vitro and in vivo.
Main Methods:
- Utilized an in vitro hydrogen peroxide (H2O2)-induced oxidative stress model in SH-SY5Y and HMC3 cells.
- Employed an in vivo controlled cortical impact (CCI) model of TBI in mice.
- Assessed cellular and molecular changes, including protein expression, inflammatory mediators, ROS levels, and signaling pathways.
Main Results:
- H2O2 increased cofilin and SSH-1 expression in microglia; CI treatment reduced this.
- CI attenuated H2O2-induced microglial activation and pro-inflammatory mediator release.
- CI protected against oxidative stress, neuronal damage, modulated apoptosis, and activated AKT and Nrf2 pathways.
- In TBI mice, CI reduced oxidative stress markers and activated Nrf2.
Conclusions:
- Cofilin inhibition demonstrates significant neuroprotective effects in both in vitro and in vivo TBI models.
- CI mitigates TBI-induced brain damage by suppressing oxidative stress and inflammatory responses.
- Targeting cofilin represents a promising therapeutic strategy for TBI management.
