Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig

Abstract

Introduction: Permanent hearing loss and tinnitus as side-effects from treatment with the anticancer drug cisplatin is a clinical problem. Ototoxicity may be reduced by co-administration of an otoprotective agent, but the results in humans have so far been modest.Aim: The present preclinical in vivo study aimed to explore the protective efficacy of hydrogen (H2) inhalation on ototoxicity induced by intravenous cisplatin.Materials and Methods: Albino guinea pigs were divided into four groups. The Cispt (n = 11) and Cispt+H2 (n = 11) groups were given intravenous cisplatin (8 mg/kg b.w., injection rate 0.2 ml/min). Immediately after, the Cispt+H2 group also received gaseous H2 (2% in air, 60 min). The H2 group (n = 5) received only H2 and the Control group (n = 7) received neither cisplatin nor H2. Ototoxicity was assessed by measuring frequency specific ABR thresholds before and 96 h after treatment, loss of inner (IHCs) and outer (OHCs) hair cells, and by performing densitometry-based immunohistochemistry analysis of cochlear synaptophysin, organic transporter 2 (OCT2), and copper transporter 1 (CTR1) at 12 and 7 mm from the round window. By utilizing metabolomics analysis of perilymph the change of metabolites in the perilymph was assessed.Results: Cisplatin induced electrophysiological threshold shifts, hair cell loss, and reduced synaptophysin immunoreactivity in the synapse area around the IHCs and OHCs. H2 inhalation mitigated all these effects. Cisplatin also reduced the OCT2 intensity in the inner and outer pillar cells and in the stria vascularis as well as the CTR1 intensity in the synapse area around the IHCs, the Deiters' cells, and the stria vascularis. H2 prevented the majority of these effects.Conclusion: H2 inhalation can reduce cisplatin-induced ototoxicity on functional, cellular, and subcellular levels. It is proposed that synaptopathy may serve as a marker for cisplatin ototoxicity. The effect of H2 on the antineoplastic activity of cisplatin needs to be further explored.

Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats

“…The main mechanisms of neonatal HIBI include oxidative stress, excitability, inflammation, and apoptosis [2]. Many researchers believe that similar to nitric oxide, hydrogen sulfide, and carbon monoxide, H 2 may be an important bioactive gas [30,31]. There are no reported side effects with H 2 , which may confer a unique advantage in disease prevention and treatment [31].…”

“…Many researchers believe that similar to nitric oxide, hydrogen sulfide, and carbon monoxide, H 2 may be an important bioactive gas [30,31]. There are no reported side effects with H 2 , which may confer a unique advantage in disease prevention and treatment [31]. In addition, human safety has been demonstrated and standards have been established for inhalation of high H 2 concentrations; high-pressure H 2 gas is used in deep diving gas mixes to prevent decompression sickness and arterial gas thrombi [32].…”

Current Strategies to Combat Cisplatin-Induced Ototoxicity

“…anti-inflammation rats, cisplatin I.P., 11 mg/kg, using an infusion pump intratympanic administration, 0.1 mM solution (50ml), 0.5 h before cisplatin injection reduced ABR threshold shifts, especially at the highest frequency. (Kaur et al, 2016) Curcumin antioxidant, anti-inflammatory rat, cisplatin I.P., 16 mg/kg I.P., 200mg/kg, 1 h before cisplatin administration and once daily for the following 3 days decreased ABR thresholds by 20-25 dB at 6-32 kHz, increased DPOAE amplitude relative to cisplatin alone (Fetoni et al, 2014) Forskolin antioxidant, anti-inflammation mice, cisplatin I.P., 3 mg/kg/ day x 7 days I.P., 1mg/kg, one day ahead and at 2h before cisplatin injection reduced ABR threshold shifts by 5-15 dB, especially at high frequency regions (Guo et al, 2018) Epigallocatechin-3-gallate (EGCG) antioxidant, anti-inflammation rats, cisplatin I.P., 11 mg/kg oral administration, 100 mg/kg/day x 4 days, 1 day before cisplatin injection reduced ABR threshold shifts (10-20dB) at 8, 16 and 32 kHz, attenuated loss of OHCs in the basal region, protected ribbon synapses and Na+/K+ ATPase a1 in SV/SL (Borse et al, 2017) Hydrogen (H2) antioxidant, anti-inflammation, increase synaptophysin guinea pigs, cisplatin I.P., 8 mg/kg gaseous H2 inhalation (2% in air, 60 min), immediately after cisplatin injection reduced ABR thresholds (-25dB) at 12.5, 20.0, and 30.0 kHz, attenuated OHC loss, protected IHC synapses (Fransson et al, 2017) N-acetylcysteine (NAC) antioxidant, anti-apoptosis rats, cisplatin I.P., 15mg/kg I.P., 500 mg/kg/day x 3 days, 4 h after cisplatin on the first day reduced ABR thresholds (-25dB) and increased DPOAE responses at all frequencies (Somdas et al, 2018) KR-22332 antioxidant, anti-apoptosis rats, cisplatin I.P., 14 mg/kg intratympanic administration, 2 mM, 0.5h before cisplatin injection reduced ABR threshold shifts (-30dB) at 8kHz (Shin et al, 2013) Pifithrin-a (PFT-a) anti-apoptosis mice, cisplatin I.P., 16 mg/kg I.P., 2.2 mg/kg, 0.5h before cisplatin injection on day 0 and daily for 5 days; I.T., 2 Mm (10ml), 0.5h before cisplatin injection on day 0 and daily for 2 days reduced ABR threshold shifts from 4-32 kHz (20-25dB) (Kim et al, 2018b) with as many as six repetitions. Multi-dose administrations that mimic clinical regimens are essential.…”

Pharmacological intervention in the field of ototoxicity

“…Since hydrogen gas is considered to have antioxidative properties, a number of researchers have examined the protection of hydrogen in reducing oxidative stress for several medical conditions. Cisplatin-induced hearing loss has been demonstrated in vivo to be limited when using inhalation of hydrogen gas [ 15 ]. One drawback is that no attempt has been made to study the effects on tumor cells after intratympanic administration or inhalation.…”