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Updated: Jul 30, 2025
A Preclinical Controlled Cortical Impact Model for Traumatic Hemorrhage Contusion and Neuroinflammation
Published on: June 10, 2020
Spatiotemporal Cofilin Signaling, Microglial Activation, Neuroinflammation, and Cognitive Impairment Following
Daniyah A Almarghalani1, Xiaojin Sha2, Robert E Mrak3
1Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA.
Insights
Cofilin overactivation in microglia may drive neuroinflammation and cognitive impairment after intracerebral hemorrhage (ICH). This study reveals cofilin signaling, microglial activation, and their link to outcomes in ICH mouse models and human brains.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Intracerebral hemorrhage (ICH) is a severe condition with high mortality.
- The role of cofilin signaling in the context of ICH, particularly over time, remains unclear.
- Microglia activation is a key feature of brain injury, but its precise relationship with cofilin in ICH needs further investigation.
Purpose of the Study:
- To investigate cofilin expression and signaling in human ICH autopsy brains.
- To longitudinally examine spatiotemporal cofilin signaling, microglia activation, and neurobehavioral outcomes in a mouse model of ICH.
- To elucidate the potential link between cofilin overactivation, microglial response, and post-stroke cognitive impairment (PSCI).
Main Methods:
- Analysis of cofilin localization in human ICH autopsy brain samples.
- Induction of ICH in mice via intrastriatal collagenase injection, followed by sacrifice at multiple time points (1-28 days).
- Assessment of neurobehavioral deficits, hematoma and ventricle volumes, cofilin and SSH1 protein expression, microglial activation markers (mRNA and morphology), and inflammatory/anti-inflammatory cytokine levels.
Main Results:
- Increased intracellular cofilin in microglia was observed in human ICH brains.
- ICH mice exhibited significant neurobehavioral deficits and PSCI, with peak deficits around day 7.
- Cofilin and SSH1 protein levels increased early post-ICH, correlating with increased microglial activation and inflammatory markers, followed by a gradual decrease.
- Blood cofilin levels rose on day 3, coinciding with increased chemokine levels.
Conclusions:
- Microglial activation following ICH may be a consequence of cofilin overactivation.
- This cofilin-mediated microglial response contributes to neuroinflammation and subsequent post-stroke cognitive impairment.
- Targeting cofilin signaling could offer a therapeutic strategy for mitigating ICH-induced brain damage and cognitive deficits.
Abstract:
Intracerebral hemorrhage (ICH) is a significant health concern associated with high mortality. Cofilin plays a crucial role in stress conditions, but its signaling following ICH in a longitudinal study is yet to be ascertained. In the present study, we examined the cofilin expression in human ICH autopsy brains. Then, the spatiotemporal cofilin signaling, microglia activation, and neurobehavioral outcomes were investigated in a mouse model of ICH. Human autopsy brain sections from ICH patients showed increased intracellular cofilin localization within microglia in the perihematomal area, possibly associated with microglial activation and morphological changes. Various cohorts of mice were subjected to intrastriatal collagenase injection and sacrificed at time points of 1, 3, 7, 14, 21, and 28 days. Mice suffered from severe neurobehavioral deficits after ICH, lasting for 7 days, followed by a gradual improvement. Mice suffered post-stroke cognitive impairment (PSCI) both acutely and in the chronic phase. Hematoma volume increased from day 1 to 3, whereas ventricle size increased from day 21 to 28. Cofilin protein expression increased in the ipsilateral striatum on days 1 and 3 and then decreased from days 7 to 28. An increase in activated microglia was observed around the hematoma on days 1 to 7, followed by a gradual reduction up to day 28. Around the hematoma, activated microglia showed morphological changes from ramified to amoeboid. mRNA levels of inflammatory [tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin-6 (IL-6) and anti-inflammatory markers [interleukin-10 (IL-10), transforming growth factor-β TGF-β, and arginase I (Arg1)] increased during the acute phase and decreased in the chronic phase. Blood cofilin levels increased on day 3 and matched the increase in chemokine levels. slingshot protein phosphatase 1 (SSH1) protein, which activates cofilin, was increased from day 1 to 7. These results suggest that microglial activation might be the sequel of cofilin overactivation following ICH, leading to widespread neuroinflammation and consequent PSCI.
