Neuregulin1 Attenuates H2O2-Induced Reductions in EAAC1 Protein Levels and Reduces H2O2-Induced Oxidative Stress

et al. 2020

Mol Brain

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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.

Section: Discussionsupporting

confidence: 53%

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

et al. 2020

Mol Brain

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“…Several lines of evidence collectively suggest that NRG1 plays a neuroprotective role in the brain against neurotoxic substances related to apoptosis and oxidative damage in neurons [41][42][43][44]. In this study, we showed that NRG1 could prevent CoCl 2 -induced upregulation of EAAC1 levels in SH-SY5Y cells.…”

Section: Discussionsupporting

confidence: 52%

Neuregulin-1 Inhibits CoCl2-Induced Excitatory Amino Acid Carrier 1 Overexpression and Oxidative Stress in SH-SY5Y Cells

et al. 2020

Preprint

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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 overexpression of EAAC1 in a dose- and time-dependent manner. We further demonstrated that pretreatment with NRG1 rescued the CoCl2-induced upregulation of EAAC1 and tau expression. Neuregulin-1 (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. Our novel findings suggest that NRG1 may play a protective role in oxidative stress and hypoxia through the regulation of EAAC1.

“…The loss of brain EAAC1 expression interferes with GABA synthesis and results in epilepsy 17,18 . EAAC1 expression is altered under pathological conditions and stimuli, such as epilepsy, hypoxia, multiple sclerosis, bipolar, schizophrenia, H 2 O 2 , retinoids, and neuregulin-1 16,[19][20][21][22][23] . Moreover, genetic studies implicate Slc1a1, a gene encoding EAAC1, in obsessive-compulsive disorder 24,25 .…”

Section: Introductionmentioning

confidence: 99%

Early-life stress induces EAAC1 expression reduction and attention-deficit and depressive behaviors in adolescent rats

et al. 2020

Cell Death Discov.

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Neonatal maternal separation (NMS), as an early-life stress (ELS), is a risk factor to develop emotional disorders. However, the exact mechanisms remain to be defined. In the present study, we investigated the mechanisms involved in developing emotional disorders caused by NMS. First, we confirmed that NMS provoked impulsive behavior, orienting and nonselective attention-deficit, abnormal grooming, and depressive-like behaviors in adolescence. Excitatory amino acid carrier 1 (EAAC1) is an excitatory amino acid transporter expressed specifically by neurons and is the route for the neuronal uptake of glutamate/aspartate/cysteine. Compared with that in the normal control group, EAAC1 expression was remarkably reduced in the ventral hippocampus and cerebral cortex in the NMS group. Additionally, EAAC1 expression was reduced in parvalbumin-positive hippocampal GABAergic neurons in the NMS group. We also found that EAAC1-knockout (EAAC1−/−) mice exhibited impulsive-like, nonselective attention-deficit, and depressive-like behaviors compared with WT mice in adolescence, characteristics similar to those of the NMS behavior phenotype. Taken together, our results revealed that ELS induced a reduction in EAAC1 expression, suggesting that reduced EAAC1 expression is involved in the pathophysiology of attention-deficit and depressive behaviors in adolescence caused by NMS.