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.