期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/ijms23010023
关键词
auditory dysfunction; tinnitus; salicylate; valproic acid; glutamate excitotoxicity; ROS; apoptosis
资金
- National Research Foundation of Korea (NRF) - Ministry of Science and ICT for Bioinspired Innovation Technology Development Project [NRF2018M3C1B7021997]
- Korea Medical Device Development Fund - Korea government (the Ministry of Science and ICT)
- Ministry of Health AMP
- Welfare, Republic of Korea
- (Ministry of Food and Drug Safety) [202013C05]
- National Research Foundation of Korea (NRF) - Korea government (MSIT) [2021R1A2C101417611]
This study investigated the therapeutic effects of valproic acid (VPA) in a salicylate-induced tinnitus model. The results showed that pretreatment with VPA before salicylate treatment can attenuate the increased levels of NMDA receptor, intracellular reactive oxygen species (ROS), and apoptosis-related markers induced by salicylate. These findings provide evidence for the beneficial effects of VPA in the treatment of salicylate-induced temporary hearing loss and tinnitus.
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 TNF alpha 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.
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