Abstract
High-dose salicylate induces temporary moderate hearing loss and the perception of a high-pitched tinnitus in humans and animals. Previous studies demonstrated that high doses of salicylate increase N-methyl-d-aspartate (NMDA) receptor levels, resulting in a rise in Ca2+ influx and induction of excitotoxicity. Glutamate excitotoxicity is associated with failure in the maintenance of calcium homeostasis, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Valproic acid (VPA) is widely used for the management of bipolar disorder, epilepsy, and migraine headaches, and is known to regulate NMDA receptor activity. In this study, we examined the beneficial effects of VPA in a salicylate-induced tinnitus model in vitro and in vivo. Cells were pretreated with VPA followed by salicylate treatment. The expression levels of NMDA receptor subunit NR2B, phosphorylated cAMP response element-binding protein—an apoptosis marker, and intracellular levels of ROS were measured using several biochemical techniques. We observed increased expression of NR2B and its related genes TNFα and ARC, increased intracellular ROS levels, and induced expression of cleaved caspase-3. These salicylate-induced changes were attenuated in the neuronal cell line SH-SY5Y and rat cortical neurons after VPA pretreatment. Together, these results provide evidence of the beneficial effects of VPA in a salicylate-induced temporary hearing loss and tinnitus model.
Highlights
NR2B expression was increased by salicylate treatment and was significantly decreased upon pretreatment with Valproic acid (VPA) according to the results of Quantitative Polymerase Chain Reaction (qPCR), immunocytochemical staining, and immunoblotting (Figure 1A–D)
The phosphorylation levels of CREB were increased in salicylate-treated cells and significantly decreased in VPA-pretreated cells, whereas the levels of CREB and the internal standard GAPDH showed no changes upon any treatment (Figure 2A,B)
We examined the expression of NR2B in the auditory cortex of the rat brain using auditory cortex are immunohistochemistry
Summary
Chronic tinnitus is an auditory phantom perception; it is defined not as a disease but as a prevalent symptom. According to epidemiological survey reports, the prevalence of tinnitus is approximately 10%–15% in the adult population. Severe tinnitus affected 1%–2% of adults and, in 0.5% of adults, it disrupted the ability to live a normal life [1,2]. The majority of sensorineural hearing loss, such as noiseinduced hearing loss or presbycusis, is accompanied by tinnitus [3]
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