Minocycline prevents gentamicin-induced ototoxicity by inhibiting p38 MAP kinase phosphorylation and caspase 3 activation.
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.
Wei
X
X
Department of Neurology, School of Medicine, Indiana University, 975 West Walnut Street IB 457, Indianapolis, IN 46202, USA.
Zhao
L
L
Liu
J
J
Dodel
R C
RC
Farlow
M R
MR
Du
Y
Y
D000818:Animals; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003051:Cochlea / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005839:Gentamicins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000201:enzymology; D008911:Minocycline / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D005839:Gentamicins; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D008911:Minocycline