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TPEN, a Specific Zn2+ Chelator, Inhibits Sodium Dithionite and Glucose Deprivation (SDGD)-Induced Neuronal Death by Modulating Apoptosis, Glutamate Signaling, and Voltage-Gated K+ and Na+ Channels

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Abstract

Hypoxia–ischemia-induced neuronal death is an important pathophysiological process that accompanies ischemic stroke and represents a major challenge in preventing ischemic stroke. To elucidate factors related to and a potential preventative mechanism of hypoxia–ischemia-induced neuronal death, primary neurons were exposed to sodium dithionite and glucose deprivation (SDGD) to mimic hypoxic–ischemic conditions. The effects of N,N,N′,N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a specific Zn2+-chelating agent, on SDGD-induced neuronal death, glutamate signaling (including the free glutamate concentration and expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor (GluR2) and N-methyl-d-aspartate (NMDA) receptor subunits (NR2B), and voltage-dependent K+ and Na+ channel currents were also investigated. Our results demonstrated that TPEN significantly suppressed increases in cell death, apoptosis, neuronal glutamate release into the culture medium, NR2B protein expression, and I K as well as decreased GluR2 protein expression and Na+ channel activity in primary cultured neurons exposed to SDGD. These results suggest that TPEN could inhibit SDGD-induced neuronal death by modulating apoptosis, glutamate signaling (via ligand-gated channels such as AMPA and NMDA receptors), and voltage-gated K+ and Na+ channels in neurons. Hence, Zn2+ chelation might be a promising approach for counteracting the neuronal loss caused by transient global ischemia. Moreover, TPEN could represent a potential cell-targeted therapy.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 31272317), the Natural Science Foundation of Tianjin City (15JCYBJC24500), and the 111 Project (B08011).

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Authors and Affiliations

  1. College of Life Sciences, Nankai University, Tianjin, 300071, People’s Republic of China

    Feng Zhang, Xue-ling Ma, Yu-xiang Wang, Cong-cong He, Kun Tian, Hong-gang Wang, Di An, Bin Heng & Yan-qiang Liu

  2. Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA

    Lai-hua Xie

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  1. Feng Zhang
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Zhang, F., Ma, Xl., Wang, Yx. et al. TPEN, a Specific Zn2+ Chelator, Inhibits Sodium Dithionite and Glucose Deprivation (SDGD)-Induced Neuronal Death by Modulating Apoptosis, Glutamate Signaling, and Voltage-Gated K+ and Na+ Channels. Cell Mol Neurobiol 37, 235–250 (2017). https://doi.org/10.1007/s10571-016-0364-1

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