Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Research Article

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

Author(s): Dongmei Gao, Hong Yu, Bo Li, Li Chen, Xiaoyu Li* and Wenqing Gu*

Volume 25, Issue 45, 2019

Page: [4820 - 4826] Pages: 7

DOI: 10.2174/1381612825666191106143743

Price: $65


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.

Keywords: Cytokine, GABA, cochlear spiral ganglion, ototoxicity, cisplatin, TNF-α.

Allen NJ, Káradóttir R, Attwell D. Reversal or reduction of glutamate and GABA transport in CNS pathology and therapy. Pflugers Arch 2004; 449(2): 132-42.
[] [PMID: 15338308]
Altun Z, Olgun Y, Ercetin P, et al. Protective effect of acetyl-l-carnitine against cisplatin ototoxicity: role of apoptosis-related genes and pro-inflammatory cytokines. Cell Prolif 2014; 47(1): 72-80.
[] [PMID: 24286513]
Arnold T, Oestreicher E, Ehrenberger K, Felix D. GABA(A) receptor modulates the activity of inner hair cell afferents in guinea pig cochlea. Hear Res 1998; 125(1-2): 147-53.
[] [PMID: 9833968]
Bauer CA, Brozoski TJ, Holder TM, Caspary DM. Effects of chronic salicylate on GABAergic activity in rat inferior colliculus. Hear Res 2000; 147(1-2): 175-82.
[] [PMID: 10962183]
Borden LA. GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem Int 1996; 29(4): 335-56.
[] [PMID: 8939442]
Callejo A, Sedó-Cabezón L, Juan ID, Llorens J. Cisplatin-induced ototoxicity: Effects, mechanisms and protection strategies. Toxics 2015; 3(3): 268-93.
[] [PMID: 29051464]
Conti F, Minelli A, Melone M. GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications. Brain Res Brain Res Rev 2004; 45(3): 196-212.
[] [PMID: 15210304]
Fujioka M, Kanzaki S, Okano HJ, Masuda M, Ogawa K, Okano H. Proinflammatory cytokines expression in noise-induced damaged cochlea. J Neurosci Res 2006; 83(4): 575-83.
[] [PMID: 16429448]
Harrison RT, DeBacker JR, Bielefeld EC. A low-dose regimen of cisplatin before high-dose cisplatin potentiates ototoxicity. Laryngoscope 2015; 125(2): E78-83.
[] [PMID: 25267530]
Jin XT, Galvan A, Wichmann T, Smith Y. Localization and function of GABA transporters GAT-1 and GAT-3 in the basal ganglia. Front Syst Neurosci 2011; 5: 63.
[] [PMID: 21847373]
Juhn SK, Rybak LP. Labyrinthine barriers and cochlear homeostasis. Acta Otolaryngol 1981; 91(5-6): 529-34.
[] [PMID: 6791457]
Kaur T, Mukherjea D, Sheehan K, Jajoo S, Rybak LP, Ramkumar V. Short interfering RNA against STAT1 attenuates cisplatin-induced ototoxicity in the rat by suppressing inflammation. Cell Death Dis 2011; 2: e180.
[] [PMID: 21776018]
Keithley EM, Wang X, Barkdull GC. Tumor necrosis factor alpha can induce recruitment of inflammatory cells to the cochlea, Otology & neurotology: official publication of the American Otological Society, American neurotology society. Euro Acad Otol Neurotol 2008; 29: 854-9.
Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 2007; 7(8): 573-84.
[] [PMID: 17625587]
Kim J, Cho HJ, Sagong B, et al. Alpha-lipoic acid protects against cisplatin-induced ototoxicity via the regulation of MAPKs and proinflammatory cytokines. Biochem Biophys Res Commun 2014; 449(2): 183-9.
[] [PMID: 24796665]
Ladrech S, Wang J, Simonneau L, Puel JL, Lenoir M. Macrophage contribution to the response of the rat organ of Corti to amikacin. J Neurosci Res 2007; 85(9): 1970-9.
[] [PMID: 17497672]
Mahgoub E, Kumaraswamy SM, Kader KH, et al. Genipin attenuates cisplatin-induced nephrotoxicity by counteracting oxidative stress, inflammation, and apoptosis. Biomed Pharmacother 2017; 93: 1083-97.
Maison SF, Rosahl TW, Homanics GE, Liberman MC. Functional role of GABAergic innervation of the cochlea: phenotypic analysis of mice lacking GABA(A) receptor subunits alpha 1, alpha 2, alpha 5, alpha 6, beta 2, beta 3, or delta. J Neurosci 2006; 26(40): 10315-26.
[] [PMID: 17021187]
Murashita H, Tabuchi K, Sakai S, Uemaetomari I, Tsuji S, Hara A. The effect of a GABAA agonist muscimol on acoustic injury of the mouse cochlea. Neurosci Lett 2007; 418(1): 18-21.
[] [PMID: 17353094]
Okano T, Nakagawa T, Kita T, et al. Bone marrow-derived cells expressing Iba1 are constitutively present as resident tissue macrophages in the mouse cochlea. J Neurosci Res 2008; 86(8): 1758-67.
[] [PMID: 18253944]
Overstreet LS, Westbrook GL. Synapse density regulates independence at unitary inhibitory synapses. J Neurosci 2003; 23(7): 2618-26.
[] [PMID: 12684447]
Ravi R, Somani SM, Rybak LP. Mechanism of cisplatin ototoxicity: antioxidant system. Pharmacol Toxicol 1995; 76(6): 386-94.
[] [PMID: 7479581]
Reijntjes DOJ, Pyott SJ. The afferent signaling complex: regulation of type I spiral ganglion neuron responses in the auditory periphery. Hear Res 2016; 336: 1-16.
[] [PMID: 27018296]
Richerson GB, Wu Y. Dynamic equilibrium of neurotransmitter transporters: not just for reuptake anymore. J Neurophysiol 2003; 90(3): 1363-74.
[] [PMID: 12966170]
Sakai S, Tabuchi K, Murashita H, Hara A. Activation of the GABA(A) receptor ameliorates the cochlear excitotoxicity caused by kainic acid in the guinea pig. Tohoku J Exp Med 2008; 215(3): 279-85.
[] [PMID: 18648188]
Semyanov A, Walker MC, Kullmann DM, Silver RA. Tonically active GABA A receptors: modulating gain and maintaining the tone. Trends Neurosci 2004; 27(5): 262-9.
[] [PMID: 15111008]
Sheth S, Mukherjea D, Rybak LP, Ramkumar V. Mechanisms of cisplatin-induced ototoxicity and otoprotection. Front Cell Neurosci 2017; 11: 338.
[] [PMID: 29163050]
So H, Kim H, Lee JH, et al. Cisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-kappaB. J Assoc Res Otolaryngol 2007; 8(3): 338-55.
[] [PMID: 17516123]
Tan BT, Lee MM, Ruan R. Bone-marrow-derived cells that home to acoustic deafened cochlea preserved their hematopoietic identity. J Comp Neurol 2008; 509(2): 167-79.
[] [PMID: 18461607]
Tang X, Zhu X, Ding B, Walton JP, Frisina RD, Su J. Age-related hearing loss: GABA, nicotinic acetylcholine and NMDA receptor expression changes in spiral ganglion neurons of the mouse. Neuroscience 2014; 259: 184-93.
[] [PMID: 24316061]
Tange RA, Vuzevski VD. Changes in the stria vascularis of the guinea pig due to cis-platinum. Arch Otorhinolaryngol 1984; 239(1): 41-7.
[] [PMID: 6537883]
Wakabayashi K, Fujioka M, Kanzaki S, et al. Blockade of interleukin-6 signaling suppressed cochlear inflammatory response and improved hearing impairment in noise-damaged mice cochlea. Neurosci Res 2010; 66(4): 345-52.
[] [PMID: 20026135]
Wang X, Truong T, Billings PB, Harris JP, Keithley EM. Blockage of immune-mediated inner ear damage by etanercept, otology & neurotology: official publication of the American otological society, American neurotology society. Euro Acad Otol Neurotol 2003; 24: 52-7.
Wu Y, Wang W, Díez-Sampedro A, Richerson GB. Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1. Neuron 2007; 56(5): 851-65.
[] [PMID: 18054861]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy