(TKP2021-EGA-23) Támogató: Innovációs és Technológiai Minisztérium
(TÉT_10-1-2011-0421)
Aminoglycoside antibiotics remain indispensable despite their ototoxicity. Like other
sensorineural forms, aminoglycoside-induced hearing loss (AGIHL) has no effective
pharmacotherapy. Oxidative stress, apoptosis, excitotoxicity and inflammation are
key pathological factors of the disease. We hypothesised that selegiline, an irreversible
monoamine oxidase-B (MAO-B) inhibitor used in Parkinson’s disease, could be repurposed
as an otoprotective agent against AGIHL and its effect on dopamine (DA) release from
lateral olivocochlear (LOC) fibres, the efferent division of a protective feedback
loop plays a major role in the protection against excitotoxicity. Selegiline mitigated
AGIHL in BALB/c mice in a dose-dependent manner at different auditory brainstem response
frequencies, including 16 kHz, the hearing sensitivity optimum of the animals. It
also enhanced the action potential-evoked DA release from LOC efferents in mouse cochlear
preparation dose-dependently. Inhibition of DA reuptake contributed to its basic effect
of saving DA from metabolism. Among four selegiline analogues tested, the one that
increased LOC DA release also provided otoprotection. In contrast, neither safinamide
(a reversible MAO-B inhibitor) nor LJP-1207 (a selective semicarbazide-sensitive amine
oxidase/vascular-adhesion protein 1 (SSAO/VAP1) inhibitor) prevented AGIHL, despite
their antioxidant and anti-inflammatory properties. The reversibility or lack of MAO-B
inhibition in safinamide and LJP-1207, respectively, as well as the absence of the
propargylamine moiety with known intrinsic neuroprotective activity in both molecules,
may explain their ineffectiveness. Selegiline, or certain propargylamine analogues
of it, offer a promising therapy against AGIHL by addressing its multifactorial pathology
through antioxidant, antiapoptotic, neuroprotective, and anti-inflammatory actions,
while enhancing endogenous DAergic protective mechanisms.
