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Cofilin Mediates LPS-Induced Microglial Cell Activation and Associated Neurotoxicity Through Activation of NF-κB and JAK–STAT Pathway

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Abstract

Microglial cells are activated in response to different types of injuries or stress in the CNS. Such activation is necessary to get rid of the injurious agents and restore tissue homeostasis. However, excessive activation of microglial cells is harmful and contributes to secondary injury. Pertinently, microglial cell activity was targeted in many preclinical and clinical studies but such strategy failed in clinical trials. The main reason behind the failed attempts is the complexity of the injury mechanisms which needs either a combination therapy or targeting a process that is involved in multiple pathways. Cofilin is a cytoskeleton-associated protein involved in actin dynamics. In our previous study, we demonstrated the role of cofilin in mediating neuronal apoptosis during OGD conditions. Previous studies on microglia have shown the involvement of cofilin in ROS formation and phagocytosis. However, additional studies are needed to delineate the role of cofilin in microglial cell activation. Therefore, in the current study, we investigated the role of cofilin in LPS-induced microglial cell activation using cofilin siRNA knockdown paradigms. The viability of differentiated PC12 cells was used as a measure of the neurotoxic potential of conditioned medium derived from cofilin siRNA-transfected and LPS-activated microglial cells. Cofilin knockdown significantly inhibited LPS-induced microglial cell activation through NF-κB and JAK–STAT pathways. The release of proinflammatory mediators (NO, TNF-α, iNOS, and COX2) as well as microglial proliferation and migration rates were significantly reduced by cofilin knockdown. Furthermore, differentiated PC12 cells were protected from the neurotoxicity induced by conditioned medium derived from cofilin-transfected and LPS-activated microglial cells. In conclusion, we demonstrated that cofilin is involved in the cascade of microglial cell activation and further validates our previous study on cofilin’s role in mediating neuronal apoptosis. Together, our results suggest that cofilin could present a common target in neurons and microglial cells and might prove to be a promising therapy for different brain injury mechanisms including stroke.

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Acknowledgements

The study was partly funded by a grant from NIH-National Complimentary and integrative health (R00AT004197) and start-up funds from The University of Toledo to ZAS. Qasim Alhadidi was supported by the Higher Committee for Education Development in Iraq (www.hcediraq.org). We would like to thank Dr. Kumi Nagamoto-Combs from the University of North Dakota for the generous gift of SIM-A9 cells. The content is solely the responsibility of the authors and does not necessarily represent the official views of funding agencies.

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  1. Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA

    Qasim Alhadidi

  2. Department of Pharmacy, Diyala Health Directorate, Ministry of Health, Baghdad, Iraq

    Qasim Alhadidi

  3. Department of Medicinal and Biological Chemistry, University of Toledo, 3000 Arlington Avenue, Toledo, OH, 43614, USA

    Zahoor A. Shah

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Alhadidi, Q., Shah, Z.A. Cofilin Mediates LPS-Induced Microglial Cell Activation and Associated Neurotoxicity Through Activation of NF-κB and JAK–STAT Pathway. Mol Neurobiol 55, 1676–1691 (2018). https://doi.org/10.1007/s12035-017-0432-7

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