Neuregulin-1 inhibits CoCl 2-induced upregulation of excitatory amino acid carrier 1 expression and oxidative stress in SH-SY5Y cells and the hippocampus of mice

Mol Brain. 2020 Nov 13;13(1):153. doi: 10.1186/s13041-020-00686-2.


Excitatory amino acid carrier 1 (EAAC1) is an important subtype of excitatory amino acid transporters (EAATs) and is the route for neuronal cysteine uptake. CoCl2 is not only a hypoxia-mimetic reagent but also an oxidative stress inducer. Here, we found that CoCl2 induced significant EAAC1 overexpression in SH-SY5Y cells and the hippocampus of mice. Transient transfection of EAAC1 reduced CoCl2-induced cytotoxicity in SH-SY5Y cells. Based on this result, upregulation of EAAC1 expression by CoCl2 is thought to represent a compensatory response against oxidative stress in an acute hypoxic state. We further demonstrated that pretreatment with Neuregulin-1 (NRG1) rescued CoCl2-induced upregulation of EAAC1 and tau expression. NRG1 plays a protective role in the CoCl2-induced accumulation of reactive oxygen species (ROS) and reduction in antioxidative enzyme (SOD and GPx) activity. Moreover, NRG1 attenuated CoCl2-induced apoptosis and cell death. NRG1 inhibited the CoCl2-induced release of cleaved caspase-3 and reduction in Bcl-XL levels. Our novel finding suggests that NRG1 may play a protective role in hypoxia through the inhibition of oxidative stress and thereby maintain normal EAAC1 expression levels.

Keywords: Apoptosis; CoCl2; EAAC1; Neuregulin-1; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cobalt
  • Excitatory Amino Acid Transporter 3 / metabolism*
  • Hippocampus / pathology*
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Microinjections
  • Neuregulin-1 / pharmacology*
  • Oxidative Stress* / drug effects
  • Phosphorylation / drug effects
  • Superoxides / metabolism
  • Up-Regulation* / drug effects
  • bcl-X Protein / metabolism
  • tau Proteins / metabolism


  • Antioxidants
  • Excitatory Amino Acid Transporter 3
  • Neuregulin-1
  • SLC1A1 protein, human
  • Slc1a1 protein, mouse
  • bcl-X Protein
  • tau Proteins
  • Superoxides
  • Cobalt
  • Caspase 3
  • cobaltous chloride