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Chemokine Fractalkine Attenuates Overactivation and Apoptosis of BV-2 Microglial Cells Induced by Extracellular ATP

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Abstract

Microglia, the resident macrophages of the central nervous system (CNS), are activated by a myriad of signaling molecules including ATP, an excitatory neurotransmitter and neuron-glial signal with both neuroprotective and neurotoxic effects. The “microglial dysfunction hypothesis” of neurodegeneration posits that overactivated microglia have a reduced neuroprotective capacity and instead promote neurotoxicity. The chemokine fractalkine (FKN), one of only two chemokines constitutively expressed in the CNS, is neuroprotective in several in vivo and in vitro models of CNS pathology. It is possible, but not yet demonstrated, that high ATP concentrations induce microglial overactivation and apoptosis while FKN reduces ATP-mediated microglial overactivation and cytotoxicity. In the current study, we examined the effects of FKN on ATP-induced microglial apoptosis and the underlying mechanisms in the BV-2 microglial cell line. Exposure to ATP induced a dose-dependent reduction in BV-2 cell viability. Prolonged exposure to a high ATP concentration (3 mM for 2 h) transformed ramified (quiescent) BV-2 cells to the amoebic state, induced apoptosis, and reduced Akt phosphorylation. Pretreatment with FKN significantly inhibited ATP-induced microglial apoptosis and transformed amoebic microglia to ramified quiescent cells. These protective effects were blocked by chemical inhibition of PI3 K, strongly implicating the PI3 K/Akt signaling pathway in FKN-mediated protection of BV-2 cells from cytotoxic ATP concentrations. Prevention of ATP-induced microglial overactivation and apoptosis may enhance the neuroprotective capacity of these cells against both acute insults and chronic CNS diseases.

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Acknowledgments

This work was supported by a grant from the Natural Science Foundation of Liaoning Province, China (No. 201202050). Authors are grateful to Dr. Ying Zhao for technical expertise and Prof. Qigui Liu, a statistical expert, for helpful discussions.

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Authors and Affiliations

  1. Department of Physiology, Dalian Medical University, Dalian, 116044, Liaoning, People’s Republic of China

    Fei Hao, Nan-Nan Zhang, Dong-Mei Zhang, Hui-Yu Bai, Bo Yuan, Hao-Yue Zhu, Huan Yu, Cong-Shu Xiao & Ai-Ping Li

  2. Institute for Brain Disorders, Dalian Medical University, Dalian, 116044, Liaoning, People’s Republic of China

    Hua Piao

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  1. Fei Hao
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  2. Nan-Nan Zhang
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Correspondence to Ai-Ping Li.

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Fei Hao and Nan-Nan Zhang contributed equally to this work.

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Hao, F., Zhang, NN., Zhang, DM. et al. Chemokine Fractalkine Attenuates Overactivation and Apoptosis of BV-2 Microglial Cells Induced by Extracellular ATP. Neurochem Res 38, 1002–1012 (2013). https://doi.org/10.1007/s11064-013-1010-7

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  • DOI: https://doi.org/10.1007/s11064-013-1010-7

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