Abstract TP337: Microglial Activation and Neuroinflammation Are Mediated by Over-Activation of Cofilin After Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a major health concern associated with high mortality and morbidity. 50% of the stroke victims die within the first month and the rest of the survivors have to deal with long-term disabilities. The understanding of the molecular mechanism of the secondary injury-induced neuroinflammation or microglial activation is not studied well. Our previous study demonstrated a major causative role of the cytoskeletal protein, cofilin in ICH-induced brain injury. We demonstrated that knockdown of cofilin in a mouse model of collagenase induced-ICH improved neurobehavioral deficits, decreased hemorrhagic volume and microglia activation. In the present study, we aimed to study the cofilin signaling up to 14 days following ICH. We subjected different cohorts of mice to intrastriatal collagenase injection-induced ICH and mice were sacrificed at different time-points of 1, 3, 7, and 14 days. Using Western blotting (WB) and quantitative real-time PCR, we observed an upregulation of cofilin protein and mRNA levels in the ipsilateral striatum on day 3 and then a decreasing trend was observed from day 7 to day 14. Using immunohistochemistry analysis, activated microglia were observed to be increased after ICH from day 1, especially around the hematoma and lasted until day 7 and there was a gradual decrease observed at day 14. Activated microglia were associated with morphological changes from ramified into an amoeboid shape particularly around the hematoma from day 1 up to day 14. Human ICH autopsy brain sections also indicated that intracellular cofilin is localized within microglia and is associated with microglia morphological changes and activation of surrounding microglia. In conclusion, we believe that cofilin overactivation plays a causative role in the activation of microglia and subsequently leads to widespread neuroinflammation following ICH. Developing cofilin inhibitors might provide novel alternatives for ICH treatment.