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

Neuroscience. 2005;131(2):513-21. doi: 10.1016/j.neuroscience.2004.11.014.


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.

MeSH terms

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


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