The p38 MAPK inhibitor SB239063 protects against noise-induced hearing loss and spiral ligament fibrocyte loss in mice

Oxidative and nitrative stress contribute to noise-induced hearing loss (NIHL), but signaling pathways linking them to spiral ligament fibrocyte (SLF) injury remain unclear. We examined mitogen-activated protein kinase (MAPK) signaling in peroxynitrite-associated SLF injury in noise-exposed mice and primary cultured SLFs and evaluated the effect of the p38 MAPK inhibitor SB239063 on NIHL. Octave-band noise centered at 8 kHz (125 dB sound pressure level for 1 h) caused persistent increases in auditory brainstem response thresholds, early increases in nitrotyrosine immunoreactivity in the cochlear lateral wall, and early phosphorylation of c-Jun N-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase 1/2 (ERK1/2). Loss of type II and IV SLFs occurred later. In primary cultured SLFs, the peroxynitrite-generating compound 3-morpholinosydnonimine (SIN-1) caused cell injury and increased JNK and p38 MAPK phosphorylation without affecting ERK1/2 phosphorylation. SB239063 reduced SIN-1-induced cell injury, whereas the JNK inhibitor SP600125 did not. Local administration of SB239063 through the round window 1 day before noise exposure reduced noise-induced p38 MAPK phosphorylation in spiral ligament tissue, NIHL, and SLF loss. These findings implicate p38 MAPK in peroxynitrite-associated SLF injury in vitro and support p38 MAPK signaling as a possible preventive target for severe NIHL.