Neuregulin-1 inhibits CoCl 2 -induced upregulation of excitatory amino acid carrier 1 expression and oxidative stress in
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RESEARCH
Neuregulin‑1 inhibits C oCl2‑induced upregulation of excitatory amino acid carrier 1 expression and oxidative stress in SH‑SY5Y cells and the hippocampus of mice Han‑Byeol Kim1†, Ji‑Young Yoo1†, Seung‑Yeon Yoo1†, Jun‑Ho Lee2, Wonseok Chang3, Hye‑Sun Kim4,5, Tai‑Kyoung Baik1* and Ran‑Sook Woo1*
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 hippocam‑ pus 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 oxida‑ tive 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 C oCl2-induced accumu‑ lation 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: CoCl2, EAAC1, Neuregulin-1, Oxidative stress, Apoptosis Introduction Excitatory amino acid carrier 1 (EAAC1, also referred to as EAAT3) is one neuronal subtype of excitatory amino acid transporter (EAAT) that is ubiquitously expressed in the central nervous system (CNS). EAAC1 can also transport cysteine at a rate comparable to that of glutamate and is the primary route for the uptake of neuronal cysteine. Cysteine is a critically important substrate *Correspondence: [email protected]; [email protected] † Han-Byeol Kim, Ji-Young Yoo and Seung-Yeon Yoo contributed equally to this work 1 Department of Anatomy and Neuroscience, College of Medicine, Eulji University, 143‑5Jung‑Gu, Yongdu‑Dong, Daejeon 301‑746, Republic of Korea Full list of author information is available at the end of the article
for the synthesis of glutathione (GSH), one of the most important intracellular antioxidants in the brain [1, 2]. Mature neurons utilize cysteine but not cystine for GSH synthesis [3, 4]. EAAC1-mediated uptake may be the major source of cysteine for GSH synthesis in mature neurons [5]. Oxidative stress is a general premonitory hallmark of numerous brain pathologies and largely contributes to the acute and chronic outcomes of CNS disorders, such as epilepsy, ischemic stroke, amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease [6]. Modulation of EAAC1 activity correlates with neuronal GSH levels [7]. Knockdown of EAAC1 reduces cysteine uptake and intracellu
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