title: N-acetyl cysteine prevents synergistic, severe toxicity from two hits of oxidative stress.
abstract: The two hit hypothesis of neurodegeneration states that cells that have been severely stressed once are more vulnerable to the negative impact of a second hit. In other words, the toxicity of two hits of severe stress may be synergistic in neurons. We previously developed a two hit model of proteotoxic neurodegeneration using the proteasome inhibitor MG132. In that study, we found that the potent antioxidant N-acetyl cysteine was able to protect against the toxicity associated with dual MG132 hits. N-acetyl cysteine has been shown to ameliorate cognitive deficits in Alzheimer's patients and to reduce the symptoms of blast injury in soldiers. These studies and many others in experimental models of neurodegeneration suggest that N-acetyl cysteine can protect neurons even when they are severely injured. In the present study, we tested the hypotheses that dual hits of hydrogen peroxide and paraquat would elicit synergistic neurodegeneration and that this extreme toxicity would be prevented by N-acetyl cysteine. The findings reveal for the first time that neuronal N2a cells are much more sensitive to oxidative stress from hydrogen peroxide treatment when they have been exposed previously to the same toxin. Two hits of hydrogen peroxide also caused severe loss of glutathione. N-acetyl cysteine attenuated the loss of glutathione and reduced the near-complete loss of cells after exposure to dual hydrogen peroxide hits. The present study supports the notion that N-acetyl cysteine can robustly protect against severe, unremitting oxidative stress in a glutathione-dependent manner.
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
authors.forename: Ajay S
authors.initials: AS
authors.lastname: Unnithan
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Rumble
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
authors.forename: Sree H
authors.initials: SH
authors.lastname: Pulugulla
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Posimo
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Gleixner
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA. Electronic address: leakr@duq.edu.
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010269:Paraquat / Q000633:toxicity
chemical_list: D000975:Antioxidants; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione; D010269:Paraquat; D000111:Acetylcysteine
keywords: Alzheimer's; Antioxidant; DMSO; Dual hit; GSH; Glutathione; N-acetyl cysteine; NAC; Parkinson's; dimethyl sulfoxide; glutathione