Neuregulin-1 inhibits CoCl2-induced upregulation of excitatory amino acid carrier 1 expression and oxidative stress in SH-SY5Y cells and the hippocampus of mice

Abstract

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.

Dysregulation of ErbB4 Signaling Pathway in the Dorsal Hippocampus after Neonatal Hypoxia-Ischemia and Late Deficits in PV+ Interneurons, Synaptic Plasticity and Working Memory

“…We report that Nrg1 acutely increases in the hippocampus following HI injury, but ErbB4 activation is decreased due to low ErbB4 protein expression, which is not addressed by TH. Although Nrg1 may be neuroprotective [21] by attenuating apoptosis [66]; these effects are only afforded if associated with ErbB4 [33,67]. Akt has also been targeted to prevent cell death [68], but the lack of ErbB4 activation and Akt phosphorylation acutely (24 h) after neonatal HI suggest a failed attempt to prevent cell death.…”

Hypoxia-Inducible Factor (HIF) in Ischemic Stroke and Neurodegenerative Disease

“…Neuregulin-1 (NRG1) regulates neural cell differentiation ( Mei and Xiong, 2008 ), neuronal growth and migration ( López-Bendito et al, 2006 ; Mahar et al, 2016 ), neurotransmission ( Neddens et al, 2009 ), and synaptic activity ( Mei and Xiong, 2008 ; Mei and Nave, 2014 ). This protein can protect neurons in ischemic stroke and under oxidative stress ( Xu et al, 2017 ; Kim et al, 2020 ; Wang et al, 2021 ). NRG1 weakens HIF-1α accumulation, inhibits HIF-1α nuclear localization, and increases and regulates neuronal hypoxic dysfunction.…”

“…NRG1 weakens HIF-1α accumulation, inhibits HIF-1α nuclear localization, and increases and regulates neuronal hypoxic dysfunction. The neuroprotective effects of NRG1 appear to result from decreased HIF-1α-mediated stabilization of the p53 protein that initiates apoptosis ( Yoo et al, 2019 ; Kim et al, 2020 ).…”

MicroRNA‑424 alleviates neurocyte injury by targeting PDCD4 in a cellular model of cerebral ischemic stroke

“…Chronic hypoxia occurs in nerve cells due to the inability to efficiently transport and utilize oxygen after CoCl 2 treatment ( 27 ). CoCl 2 induced a series of changes in nerve cells similar to the effects of hypoxia ( 28 ). Therefore, CoCl 2 is an ideal compound for establishing a chronic hypoxia model.…”