Efficacy of three drugs for protecting against gentamicin-induced hair cell and hearing losses.
BACKGROUND AND PURPOSE Exposure to an ototoxic level of an aminoglycoside can result in hearing loss. In this we study investigated the otoprotective efficacy of dexamethasone (DXM), melatonin (MLT) and tacrolimus (TCR) in gentamicin (GM)-treated animals and cultures. EXPERIMENTAL APPROACH Wistar rats were divided into controls (treated with saline); exposed to GM only (GM); and three GM-exposed groups treated with either DXM, MLT or TCR. Auditory function and cochlear surface preparations were studied. In vitro studies of oxidative stress, pro-inflammatory cytokine mRNA levels, the MAPK pathway and caspase-3 activation were performed in organ of Corti explants from 3-day-old rats. KEY RESULTS DXM, MLT and TCR decreased levels of reactive oxygen species in GM-exposed explants. The mRNA levels of TNF-α, IL-1β and TNF-receptor type 1 were significantly reduced in GM + DXM and GM + MLT groups. Phospho-p38 MAPK levels decreased in GM + MLT and GM + TCR groups, while JNK phosphorylation was reduced in GM + DXM and GM + MLT groups. Caspase-3 activation decreased in GM + DXM, GM + MLT and GM + TCR groups. These results were consistent with in vivo results. Local treatment of GM-exposed rat cochleae with either DXM, MLT or TCR preserved auditory function and prevented auditory hair cell loss. CONCLUSIONS AND IMPLICATIONS In organ of Corti explants, GM increased oxidative stress and initiated an inflammatory response that led to the activation of MAPKs and apoptosis of hair cells. The three compounds tested demonstrated otoprotective properties that could be beneficial in the treatment of ototoxicity-induced hearing loss.
Hospital Clinico Universitario Research Foundation, Valencia, Spain.
E
E
Bas
T R
TR
Van De Water
C
C
Gupta
J
J
Dinh
L
L
Vu
F
F
Martínez-Soriano
J M
JM
Láinez
J
J
Marco
D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D002374:Catalase / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D005839:Gentamicins / Q000009:adverse effects*; D034381:Hearing Loss / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009925:Organ of Corti / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D053583:Interleukin-1beta; D020011:Protective Agents; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I; D047888:Receptors, Tumor Necrosis Factor, Type I; C506237:Tnfrsf1a protein, rat; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003907:Dexamethasone; D002374:Catalase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D008550:Melatonin; D016559:Tacrolimus