Cisplatin Toxicology: The Role of Pro-inflammatory Cytokines and GABA Transporters in Cochlear Spiral Ganglion.

Abstract

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.

• Authors: Dongmei Gao, Hong Yu, Bo Li, Li Chen, Xiaoyu Li, Wenqing Gu
• Journal: Current pharmaceutical design (Curr Pharm Des) Vol. 25 Issue 45 Pg. 4820-4826 ( 2019) ISSN: 1873-4286 [Electronic] United Arab Emirates
• PMID: 31692421 (Publication Type: Journal Article)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Cytokines
• GABA Plasma Membrane Transport Proteins
• Cisplatin

Topics

• Animals
• Cisplatin (toxicity)
• Cochlea (innervation)
• Cytokines (physiology)
• GABA Plasma Membrane Transport Proteins (physiology)
• Ototoxicity
• Rats
• Spiral Ganglion (drug effects)