title: Protective effect of rasagiline in aminoglycoside ototoxicity.
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 16kHz, 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(+)-, Ca(2+) 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.
authors: Department of Otorhinolaryngology, Head and Neck Surgery, Semmelweis University, Budapest, Hungary; Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors: G
authors: G
authors: Polony
authors: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors: V
authors: V
authors: Humli
authors: Department of Otorhinolaryngology, Head and Neck Surgery, Semmelweis University, Budapest, Hungary.
authors: R
authors: R
authors: Andó
authors: Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors: M
authors: M
authors: Aller
authors: Department of Otorhinolaryngology, Bajcsy-Zsilinszky Hospital, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors: T
authors: T
authors: Horváth
authors: Department of Biomathematics and Informatics, Szent István University, Budapest, Hungary.
authors: A
authors: A
authors: Harnos
authors: Department of Otorhinolaryngology, Head and Neck Surgery, Semmelweis University, Budapest, Hungary.
authors: L
authors: L
authors: Tamás
authors: Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors: E S
authors: ES
authors: Vizi
authors: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. Electronic address: zelles.tibor@med.semmelweis-univ.hu.
authors: T
authors: T
authors: Zelles
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D003051:Cochlea / Q000187:drug effects; D004298:Dopamine / Q000032:analysis; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000188:drug therapy*; D007189:Indans / Q000627:therapeutic use*; D007612:Kanamycin / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; C031967:rasagiline; D007612:Kanamycin; D004298:Dopamine
keywords: auditory brainstem response; dopamine; kanamycin; lateral olivocochlear efferents; rasagiline; sensorineural hearing loss