Dongmei Gao, Hong Yu, Bo Li, Li Chen, Xiaoyu Li* and Wenqing Gu* Pages 4820 - 4826 ( 7 )
Background: The current study was conducted to examine the specific activation of pro-inflammatory cytokines (PICs), namely IL-1β, IL-6 and TNF-α in the cochlear spiral ganglion of rats after ototoxicity induced by cisplatin. Since γ-aminobutyric acid (GABA) and its receptors are involved in pathophysiological processes of ototoxicity, we further examined the role played by PICs in regulating expression of GABA transporter type 1 and 3 (GAT-1 and GAT-3), as two essential subtypes of GATs responsible for the regulation of extracellular GABA levels in the neuronal tissues.
Methods: ELISA and western blot analysis were employed to examine the levels of PICs and GATs; and auditory brainstem response was used to assess ototoxicity induced by cisplatin. Results: IL-1β, IL-6 and TNF-α as well as their receptors were significantly increased in the spiral ganglion of ototoxic rats as compared with sham control animals (P<0.05, ototoxic rats vs. control rats). Cisplatin-ototoxicity also induced upregulation of the protein levels of GAT-1 and GAT-3 in the spiral ganglion (P<0.05 vs. controls). In addition, administration of inhibitors to IL-1β, IL-6 and TNF-α attenuated amplification of GAT-1 and GAT-3 and improved hearing impairment induced by cisplatin. Conclusion: Our data indicate that PIC signals are activated in the spiral ganglion during cisplatin-ototoxicity which thereby leads to upregulation of GABA transporters. As a result, it is likely that de-inhibition of GABA system is enhanced in the cochlear spiral ganglion. This supports a role for PICs in engagement of the signal mechanisms associated with cisplatin-ototoxicity, and has pharmacological implications to target specific PICs for GABAergic dysfunction and vulnerability related to cisplatin-ototoxicity.Cytokine, GABA, cochlear spiral ganglion, ototoxicity, cisplatin, TNF-α.
Department of Otorhinolaryngology, The First Hospital of Jilin University, Changchun, Jilin 130021, Department of Otorhinolaryngology, The First Hospital of Jilin University, Changchun, Jilin 130021, Department of Rehabilitation, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, Hospital of Stomatology, Jilin University, Changchun, Jilin 130000, Department of Otorhinolaryngology, The First Hospital of Jilin University, Changchun, Jilin 130021, Department of Otorhinolaryngology, The First Hospital of Jilin University, Changchun, Jilin 130021