Abstract
Neuregulin 1 (NRG1) exhibits potent neuroprotective properties. The aim of the present study was to investigate the antioxidative effects and underlying mechanisms of NRG1 against H2O2-induced oxidative stress in primary rat cortical neurons. The expression level of the excitatory amino acid carrier 1 (EAAC1) protein was measured by Western blotting and immunocytochemistry. The levels of lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, superoxide dismutase (SOD) activity, GPx activity, and mitochondrial membrane potential (∆ψm) were determined to examine cell death and the antioxidant properties of NRG1 in primary rat cortical neurons. H2O2 reduced the expression of EAAC1 in a dose-dependent manner. We found that pretreatment with NRG1 attenuated the H2O2-induced reduction in EAAC1 expression. Moreover, NRG1 reduced the cell death and oxidative stress induced by H2O2. In addition, NRG1 attenuated H2O2-induced reductions in antioxidant enzyme activity and ∆ψm. Our data indicate a role for NRG1 in protecting against oxidative stress via the regulation of EAAC1. These observations may provide novel insights into the mechanisms of NRG1 activity during oxidative stress and may reveal new therapeutic targets for regulating the oxidative stress associated with various neurological diseases.
Highlights
Evidence of oxidative stress in the brain has been reported for aging and a variety of neurological and neurodegenerative diseases
excitatory amino acid carrier 1 (EAAC1) is believed to be important for the synthesis of intracellular glutathione and for subsequent protection from oxidative stress
We tested whether H2O2 regulated EAAC1 protein levels in rat primary cortical neurons
Summary
Evidence of oxidative stress in the brain has been reported for aging and a variety of neurological and neurodegenerative diseases. Oxidative stress is characterized by excessive production of reactive oxygen species (ROS) and a lack of ROS clearance and is known to cause lipid peroxidation, Excitatory amino acid transporters (EAATs) regulate glutamatergic signaling by taking up glutamate from synaptic clefts into the cells. EAAT1 (glutamateaspartate transporter, GLAST) and EAAT2 (glutamate transporter-1, GLT1) are expressed in glial cells and are mainly involved in synaptic glutamate clearance, while EAAT3 (excitatory amino acid carrier 1, EAAC1) is predominantly expressed in neurons but is expressed in other types of cells. Cysteine transport via EAAC1 is considered key for neuronal GSH synthesis. GSH is Neurotox Res (2019) 35:401–409 important for the metabolism of hydrogen peroxide (H2O2), nitric oxide, and other reactive oxygen species and for the maintenance of reduced thiol groups on proteins (Dringen 2000). EAAC1 expression is altered in pathological conditions such as schizophrenia, hypoxia/ischemia, multiple sclerosis, and epilepsy (Bauer et al 2008; Bianchi et al 2014; Crino et al 2002; Romera et al 2004)
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