Neuroprotection of vestibular sensory cells from gentamicin ototoxicity obtained using nitric oxide synthase inhibitors, reactive oxygen species scavengers, brain-derived neurotrophic factors and calpain inhibitors.
OBJECTIVE
In order to devise a new treatment for inner ear disorders, the efficacy of a nitric oxide synthase inhibitor (L-N(G)-nitroarginine methylester [L-NAME]), a radical scavenger (D-methionine), a neurotrophin (brain-derived neurotrophic factor [BDNF]) and a calpain inhibitor (leupeptin) for protection from hair cell damage was investigated.


METHODS
The effects of these drugs on gentamicin-induced production of nitric oxide (NO) and reactive oxygen species (ROS) were studied by means of the fluorescence indicators 4,5-diaminofluorescein diacetate and dihydrotetramethylrosamine. The effect on gentamicin-induced vestibular hair cell damage was examined by using an in vitro LIVE/DEAD system.


RESULTS
L-NAME inhibited the production of NO, D-methionine and BDNF restricted the production of ROS and leupeptin inhibited neither NO nor ROS. All the drugs used limited the vestibular hair cell damage caused by gentamicin. The combinations L-NAME + BDNF, L-NAME + leupeptin and D-methionine + BDNF had a significantly stronger preventive effect on hair cell damage.


CONCLUSIONS
It is suggested that combined treatment with a radical inhibitor and either a neurotrophin or calpain inhibitor may help to treat inner ear disorders more effectively.
Takumida
Masaya
M
Department of Otolaryngology, Hiroshima University Faculty of Medicine, Hiroshima, Japan. masati@hiroshima-u.ac.jp
Anniko
Matti
M
Shimizu
Akira
A
Watanabe
Hiroshi
H
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005839:Gentamicins / Q000633:toxicity*; D006168:Guinea Pigs; D018069:Hair Cells, Vestibular / Q000187:drug effects* / Q000201:enzymology; D066298:In Vitro Techniques; D007976:Leupeptins / Q000494:pharmacology*; D008715:Methionine / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D016166:Free Radical Scavengers; D005839:Gentamicins; D007976:Leupeptins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D008715:Methionine; D019001:Nitric Oxide Synthase; D002154:Calpain; C032854:leupeptin; D019331:NG-Nitroarginine Methyl Ester