Salicylate-induced degeneration of cochlea spiral ganglion neurons-apoptosis signaling

Abstract

Aspirin, whose active ingredient is sodium salicylate, is the most widely used drug worldwide, but it is not recommended for children because it may cause Reye's syndrome. High doses of salicylate also induce temporary hearing loss and tinnitus; while these disorders are believed to disappear when treatment is discontinued some data suggest that prolonged treatment may be neurotoxic. To investigate its ototoxicity, immature, postnatal day 3 rat cochlear organotypic cultures were treated with salicylate. Salicylate did not damage the sensory hair cells, but instead damaged the spiral ganglion neurons (SGN) and their peripheral fibers in a dose-dependent manner. The cross-sectional area of SGN decreased from 205 μm2 in controls to 143, 116, and 91 μm2 in cultures treated with 1, 3, or 5 mM salicylate, respectively. Morphological changes and caspase upregulation were indicative of caspase-mediated apoptosis. A quantitative RT-PCR apoptosis array identified a subset of genes up- or down regulated by salicylate. Eight genes showed a biologically relevant change (P<0.05, ≥2 fold change) after 3 h treatment with salicylate; seven genes (Tp53, Birc3, Tnfrsf5, Casp7, Nfkb1, Fas, Lta, Tnfsf10) were upregulated and one gene (Pycard) was downregulated. After 6 h treatment, only one gene (Nol3) was upregulated and two genes were downregulated (Cideb and Lhx4) while after 12 h treatment, two genes (Il10, Gadd45a) were upregulated and 4 (Prok2, Card10, Ltbr, Dapk1) were downregulated. High doses of salicylate in a physiologically relevant range can induce caspase-mediated cell death in immature SGN; changes in the expression of apoptotic genes particularly among members of the tumor necrosis factor (TNF) family appear to play an important role in the degeneration.