Minocycline prevents gentamicin-induced ototoxicity by inhibiting p38 MAP kinase phosphorylation and caspase 3 activation.

Abstract

Aminoglycosides are commonly used antibiotics that often induce ototoxicity leading to permanent hair cell loss and hearing impairment. We hereby examined whether minocycline protects hair cells from gentamicin-induced hair cell damage. Two millimolar gentamicin significantly induced outer hair cell damage and the addition of minocycline to gentamicin-treated explants significantly increased hair cell survival in a dose-dependent manner. Additionally, we demonstrated that gentamicin induced p38 MAPK phosphorylation, cytochrome c release, and caspase 3 activation in these cells and these remarkable changes were blocked by minocycline treatments. Furthermore, we showed that the inhibitor of p38 MAPK or the inhibitor of caspase 3 only partially blocked gentamicin-induced hair cell damage, and the pretreatment of explants with the inhibitor of p38 MAPK and the inhibitor of caspase 3 together exerted a synergic protective effect against gentamicin-induced hair cell damage. Our results suggest that minocycline blocks gentamicin-induced hair cell loss possibly by inhibition of three mechanisms: p38 MAPK phosphorylation, cytochrome c release, and caspase 3 activation. This finding may explain why minocycline has protective activity in a variety of apoptotic models. Therapeutic intervention by using minocycline or related drugs may be a novel means for preventing inner ear injury following the use of aminoglycoside.

• Authors: X Wei, L Zhao, J Liu, R C Dodel, M R Farlow, Y Du
• Journal: Neuroscience (Neuroscience) Vol. 131 Issue 2 Pg. 513-21 ( 2005) ISSN: 0306-4522 [Print] United States
• PMID: 15708492 (Publication Type: Journal Article)

Chemical References

• Caspase Inhibitors
• Enzyme Inhibitors
• Gentamicins
• p38 Mitogen-Activated Protein Kinases
• Casp3 protein, rat
• Caspase 3
• Caspases
• Minocycline

Topics

• Animals
• Caspase 3
• Caspase Inhibitors
• Caspases (metabolism)
• Cell Survival (drug effects, physiology)
• Cochlea (drug effects, enzymology)
• Enzyme Activation (drug effects, physiology)
• Enzyme Inhibitors (pharmacology)
• Gentamicins (antagonists & inhibitors, toxicity)
• Hair Cells, Auditory (drug effects, enzymology)
• Minocycline (pharmacology)
• Phosphorylation (drug effects)
• Rats
• Rats, Sprague-Dawley
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)