Protective effect of rasagiline in aminoglycoside ototoxicity

G. Polony, V. Humli, R. Andó, M. Aller, T. Horváth, A. Harnos, L. Tamás, E. Vízi, T. Zelles

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Sensorineural hearing losses (SNHLs; e.g., ototoxicant- and noise-induced hearing loss or presbycusis) are among the most frequent sensory deficits, but they lack effective drug therapies. The majority of recent therapeutic approaches focused on the trials of antioxidants and reactive oxygen species (ROS) scavengers in SNHLs. The rationale for these studies was the prominent role of disturbed redox homeostasis and the consequent ROS elevation. Although the antioxidant therapies in several animal studies seemed to be promising, clinical trials have failed to fulfill expectations. We investigated the potential of rasagiline, an FDA-approved monomanine oxidase type B inhibitor (MAO-B) inhibitor type anti-parkinsonian drug, as an otoprotectant. We showed a dose-dependent alleviation of the kanamycin-induced threshold shifts measured by auditory brainstem response (ABR) in an ototoxicant aminoglycoside antibiotic-based hearing loss model in mice. This effect proved to be statistically significant at a 6-mg/kg (s.c.) dose. The most prominent effect appeared at 16. kHz, which is the hearing sensitivity optimum for mice. The neuroprotective, antiapoptotic and antioxidant effects of rasagiline in animal models, all targeting a specific mechanism of aminoglycoside injury, may explain this otoprotection. The dopaminergic neurotransmission enhancer effect of rasagiline might also contribute to the protection. Dopamine (DA), released from lateral olivocochlear (LOC) fibers, was shown to exert a protective action against excitotoxicity, a pathological factor in the aminoglycoside-induced SNHL. We have shown that rasagiline enhanced the electric stimulation-evoked release of DA from an acute mouse cochlea preparation in a dose-dependent manner. Using inhibitors of voltage-gated Na+-, Ca2+ channels and DA transporters, we revealed that rasagiline potentiated the action potential-evoked release of DA by inhibiting the reuptake. The complex, multifactorial pathomechanism of SNHLs most likely requires drugs acting on multiple targets for effective therapy. Rasagiline, with its multi-target action and favorable adverse effects profile, might be a good candidate for a clinical trial testing the otoprotective indication.

Original languageEnglish
Pages (from-to)263-273
Number of pages11
JournalNeuroscience
Volume265
DOIs
Publication statusPublished - Apr 18 2014

Fingerprint

Aminoglycosides
Dopamine
Antioxidants
Reactive Oxygen Species
Presbycusis
Clinical Trials
Noise-Induced Hearing Loss
Dopamine Plasma Membrane Transport Proteins
Kanamycin
Monoamine Oxidase Inhibitors
Brain Stem Auditory Evoked Potentials
Sensorineural Hearing Loss
Cochlea
Monoamine Oxidase
Neuroprotective Agents
Hearing Loss
Synaptic Transmission
Pharmaceutical Preparations
Electric Stimulation
Hearing

Keywords

  • Auditory brainstem response
  • Dopamine
  • Kanamycin
  • Lateral olivocochlear efferents
  • Rasagiline
  • Sensorineural hearing loss

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Polony, G., Humli, V., Andó, R., Aller, M., Horváth, T., Harnos, A., ... Zelles, T. (2014). Protective effect of rasagiline in aminoglycoside ototoxicity. Neuroscience, 265, 263-273. https://doi.org/10.1016/j.neuroscience.2014.01.057

Protective effect of rasagiline in aminoglycoside ototoxicity. / Polony, G.; Humli, V.; Andó, R.; Aller, M.; Horváth, T.; Harnos, A.; Tamás, L.; Vízi, E.; Zelles, T.

In: Neuroscience, Vol. 265, 18.04.2014, p. 263-273.

Research output: Contribution to journalArticle

Polony, G, Humli, V, Andó, R, Aller, M, Horváth, T, Harnos, A, Tamás, L, Vízi, E & Zelles, T 2014, 'Protective effect of rasagiline in aminoglycoside ototoxicity', Neuroscience, vol. 265, pp. 263-273. https://doi.org/10.1016/j.neuroscience.2014.01.057
Polony G, Humli V, Andó R, Aller M, Horváth T, Harnos A et al. Protective effect of rasagiline in aminoglycoside ototoxicity. Neuroscience. 2014 Apr 18;265:263-273. https://doi.org/10.1016/j.neuroscience.2014.01.057
Polony, G. ; Humli, V. ; Andó, R. ; Aller, M. ; Horváth, T. ; Harnos, A. ; Tamás, L. ; Vízi, E. ; Zelles, T. / Protective effect of rasagiline in aminoglycoside ototoxicity. In: Neuroscience. 2014 ; Vol. 265. pp. 263-273.
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