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N-Acetylcysteine Induces Apoptotic, Oxidative and Excitotoxic Neuronal Death in Mouse Cortical Cultures

Authors
  • Hwang, Shinae
  • Kim, Jong-Keun
Type
Published Article
Journal
Chonnam Medical Journal
Publisher
Chonnam National University Medical School
Publication Date
Jan 25, 2022
Volume
58
Issue
1
Pages
18–23
Identifiers
DOI: 10.4068/cmj.2022.58.1.18
PMID: 35169555
PMCID: PMC8813647
Source
PubMed Central
Keywords
Disciplines
  • Original Article
License
Unknown

Abstract

N-acetylcysteine (NAC) has been used as an antioxidant to prevent oxidative cell death. However, we found NAC itself to induce neuronal death in mouse cortical cultures. Therefore, the current study was performed to investigate the mechanism of neuronal death caused by NAC. Cell death was assessed by measuring lactate dehydrogenase efflux to bathing media after 24-48 h exposure to NAC. NAC (0.1-10 mM) induced neuronal death in a concentration- and exposure time-dependent manner. However, NAC did not injure astrocytes even at a concentration of 10 mM. Also, 10 mM NAC markedly attenuated oxidative astrocyte death induced by 0.5 mM diethyl maleate or 0.25 mM H2O2. The NMDA receptor antagonist MK-801 (10 µM) markedly attenuated the neuronal death caused by 10 mM NAC, while NBQX did not affect the neuronal death. Cycloheximide (a protein synthesis inhibitor, 0.1 µg/mL) and z-VAD-FMK (a caspase inhibitor, 100 µM) also significantly attenuated neuronal death. Apoptotic features such as chromatin condensation, nuclear fragmentation, and caspase 3 activation were observed 1 h after the NAC treatment. The neuronal death induced by 1 or 10 mM NAC was significantly attenuated by the treatment with 100 µM Trolox or 1 mM ascorbic acid. NAC induced the generation of intracellular reactive oxygen species (ROS), as measured by the fluorescent dye 2′,7′-dichlorofluorescein diacetate. The ROS generation was almost completely abolished by treatment with Trolox or ascorbic acid. These findings demonstrate that NAC can cause oxidative, apoptotic, and excitotoxic neuronal death in mouse neuronal cultures.

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