Efficacy of three drugs for protecting against gentamicin-induced hair cell and hearing losses

BACKGROUND AND PURPOSEExposure 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 APPROACHWistar 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 RESULTSDXM, 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 IMPLICATIONSIn 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

Ornithine decarboxylase activity during development of the mouse inner ear in vivo and in vitro

Ornithine decarboxylase activity was determined during the development of the peripheral auditory system in the murine otocyst with the goal of understanding the role of this enzyme in the morphological and functional maturation of the inner ear. At gestational days 11 and 12 enzyme activity was more than 10-fold higher than adult levels. A sharp decline occured between day 12 and 13 after which activity rose to a peak around day 15. Activity then dropped continuously until near-adult levels were reached at birth. A lower specific activity of ODC but a similar time-course was seen in otocysts explanted at gestational day 13 and subsequently cultured for 6 days. For two stages of development, enzyme activity and binding of 3 H-α-difluoromethylornithine were compared. The four-fold difference in enzymatic activity on gestational days 15 and 17 was paralleled by a similar difference in binding. Ornithine decarboxylase activity during inner ear development therefore seems primarily regulated at the level of protein synthesis. Ornithine decarboxylase activity correlates with major inductive events in the morphogenesis of the cartilagenous otic capsule that serves as a template for the formation of the bony labyrinth. The pattern of activity may reflect the changes in the head mesenchyme that is recruited by the otocyst to aggregate and form its protective otic capsule.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47689/1/441_2004_Article_BF00340878.pd

Transforming Growth Factor Beta: Does it Direct Otic Capsule Formation?

Interactions between the epithelium of the otocyst and surrounding periotic mesenchyme direct the formation of the capsule of the mammalian inner ear. In the present study, we have characterized the temporal-spatial distribution of transforming growth factor beta 1 (TGF-β1) in the epithelial and mesenchymal tissues that compose the inner ear between 10 and 14 days of embryonic development. In addition, using high-density cultures of periotic mesenchyme to model otic capsule formation, we have demonstrated that exogenous TGF-β1 can modulate otic chondrogenesis by acting as either an enhancer or a suppressor of this process. Our immunohistochemical and in vitro results suggest a paracrine action for this growth factor in modulation of epithelial-mesenchymal tissue interactions and otic morphogenesis

Inductive tissue interactions during inner ear development

Inductive tissue interactions were studied in the otocyst of the CBA/CBA mouse. Otocysts with surrounding mesenchyme explanted at the 12.5–13th gestational day and cultured in vitro for 4 days underwent morphogenesis with formation of semicircular canals, vestibular organs, and some cochlear coiling. Without their surrounding mesenchyme only little, if any, development was seen. However, otocysts without mesenchyme but grown in a medium precultured with mesenchyme did develop normally. A soluble and diffusible induction factor is apparently produced by mesenchyme and also by other fetal organs. Cell-cell contact may not be needed for induction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47267/1/405_2004_Article_BF00464341.pd