Nuclear-factor kappa B (NF-kappa B)-inducible nitric oxide synthase (iNOS/NOS II) pathway damages the stria vascularis in cisplatin-treated mice.
BACKGROUND
Cisplatin is reported to damage the stria vascularis of the cochlea. Free radicals, especially large amounts of nitric oxide catalyzed by inducible nitric oxide synthase, are considered to have an important role in this toxicity. The induction of inducible nitric oxide synthase is regulated by nuclear-factor kappa B (NF-kappa B). We examined the damage of the stria vascularis by immunohistochemical techniques.


METHODS
Cisplatin (15 mg/kg b.w.) was injected intraperitoneally into the mice. Three days after the injection, the cochleas were immunohistochemically-stained using specific antibodies for nuclear-factor kappa B (NF-kappa B), inducible nitric oxide synthase (iNOS) or single-stranded DNA.


RESULTS
NF-kappa B was expressed in the cisplatin-treated cochlea, especially in the stria vascularis and the spiral ligament. iNOS was also expressed in the stria vascularis and the spiral ligament. Fragments of DNA were observed only in the stria vascularis.


CONCLUSIONS
The large amounts of NO catalyzed by iNOS led to inner ear dysfunction. Our results indicate that apoptosis is triggered by iNOS and that it mediates the ototoxicity induced by cisplatin.
Watanabe
Ken-Ichi
K
Department of Oto-Rhino-Laryngology, Nippon Medical School, Sendagi 1-1-5, Bunkyo-ku, Tokyo 113-8603, Japan.
Inai
Shunta
S
Jinnouchi
Ken
K
Bada
Shunkichi
S
Hess
Alexander
A
Michel
Olaf
O
Yagi
Toshiaki
T
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity*; D015834:Cochlear Diseases / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D013316:Stria Vascularis / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D000970:Antineoplastic Agents; D004277:DNA, Single-Stranded; D016328:NF-kappa B; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D002945:Cisplatin