l-N-acetylcysteine protects outer hair cells against TNFα initiated ototoxicity in vitro.

Abstract

OBJECTIVE:

The present study is aimed at determining the efficacy and exploring the mechanisms by which l-N-acetylcysteine (l-NAC) provides protection against tumor necrosis factor-alpha (TNFα)-induced oxidative stress damage and hair cell loss in 3-day-old rat organ of Corti (OC) explants. Previous work has demonstrated a high level of oxidative stress in TNFα-challenged OC explants. TNFα can potentially play a significant role in hair cell loss following an insult to the inner ear. l-NAC has shown to provide effective protection against noise-induced hearing loss in laboratory animals but mechanisms of this otoprotective effect are not well-defined.

DESIGN:

Rat OC explants were exposed to either: (1) saline control (N = 12); (2) TNFα (2 μg/ml, N = 12); (3) TNFα+l-NAC (5 mM, N = 12); (4) TNFα+l-NAC (10 mM, N = 12); or (5) l-NAC (10 mM, N = 12). Outer hair cell (OHC) density, levels of reactive oxygen species (ROS), lipid peroxidation of cell membranes, gluthathione activity, and mitochondrial viability were assayed.

RESULTS:

l-NAC (5 and 10 mM) provided protection for OHCs from ototoxic level of TNFα in OC explants. Groups treated with TNFα+l-NAC (5 mM) showed a highly significant reduction of both ROS (p < 0.01) and 4-hydroxy-2-nonenal immunostaining (p < 0.001) compared to TNFα-challenged explants. Total glutathione levels were low in TNFα-challenged explants compared to control and TNFα+l-NAC (5 mM) treated explants (p < 0.001).

CONCLUSIONS:

l-NAC is a promising treatment for protecting auditory HCs from TNFα-induced oxidative stress and subsequent loss via programmed cell death.

• Authors: Joshua A Tillinger, Chhavi Gupta, Kadri Ila, Jamal Ahmed, Jeenu Mittal, Thomas R Van De Water, Adrien A Eshraghi
• Journal: Acta oto-laryngologica (Acta Otolaryngol) Vol. 138 Issue 8 Pg. 676-684 (Aug 2018) ISSN: 1651-2251 [Electronic] England
• PMID: 29513056 (Publication Type: Journal Article)

Chemical References

• Aldehydes
• Free Radical Scavengers
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• Glutathione Synthase
• Glutathione
• 4-hydroxy-2-nonenal
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology, therapeutic use)
• Aldehydes
• Animals
• Drug Evaluation, Preclinical
• Free Radical Scavengers (pharmacology, therapeutic use)
• Glutathione (metabolism)
• Glutathione Synthase (metabolism)
• Hair Cells, Auditory, Outer (drug effects)
• Hearing Loss (metabolism, prevention & control)
• In Vitro Techniques
• Membrane Potential, Mitochondrial (drug effects)
• Oxidative Stress (drug effects)
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Tumor Necrosis Factor-alpha