Cofilin Signaling in Hemorrhagic Stroke

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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.