Microglial Integrity is Maintained by Erythropoietin Through Integration of Akt and Its Substrates of lycogen Synthase Kinase-3β, β-Catenin, and Nuclear Factor-κB

Author(s): Faqi Li , Zhao Zhong Chong , Kenneth Maiese .

Journal Name: Current Neurovascular Research

Volume 3 , Issue 3 , 2006

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Abstract:

Recognized as a robust cytoprotectant for multiple tissues of the hematopoietic, vascular, cardiac, and nervous systems, erythropoietin (EPO) also is considered to be an attractive therapeutic candidate to modulate inflammatory cell function and survival during neurodegenerative disorders. To this end, microglia of the central nervous system serve a complex function not only to dispense of foreign organisms and injured cells of the brain, but also to foster tissue repair and reorganization during neuronal and vascular cell insults. We therefore examined the ability of EPO to modulate microglial cell survival and the underlying signal transduction pathways that govern microglial integrity during oxygenglucose deprivation (OGD) - induced oxidative stress. We demonstrate in the microglial cell line EOC 2 that EPO provides direct microglial protection against early and late apoptotic programs of membrane phosphatidylserine exposure and genomic DNA degradation. Furthermore, expression and activation of Akt1 is vital to the cytoprotective capacity of EPO, since pharmacological inhibition of the PI 3-K pathway or gene silencing of Akt1 expression eliminates the ability of EPO to protect microglial cells. Through Akt1 dependent mechanisms that can be abrogated through the gene silencing of Akt1, maintenance of microglial cell integrity during OGD by EPO is closely integrated with the phosphorylation and inhibition of glycogen synthase kinase-3β activity as well as the intracellular trafficking of β-catenin and nuclear factor-κB. Further work that continues to elucidate the ability of EPO to target the intricate pathways that determine inflammatory cell function and integrity may lay the ground work for new therapeutic avenues for neurodegenerative disease.

Keywords: Akt1, apoptosis, gene silencing, GSK-3β, inflammation, microglia, NF-κB, oxygen-glucose deprivation, protein kinase B, oxidative stress

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Article Details

VOLUME: 3
ISSUE: 3
Year: 2006
Page: [187 - 201]
Pages: 15
DOI: 10.2174/156720206778018758
Price: $58

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