Neurochemistry and Neuropharmacology
Author: Lucia Agüero | Email: lucia@ague.ro
Lucia Agüero1°, Sofía Ludmila Gallino1°, María Eugenia Gomez Casati2°, Paula Inés Buonfiglio1°, Viviana Karina Dalamon1°, Ana Belén Elgoyhen1°2°
1° Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr Héctor N. Torres
2° Instituto de Farmacología, Facultad de Medicina, UBA
Hearing loss affects 360 million people (5% of the world’s population and 42% of those over 75). While half of hearing loss has a genetic origin, the other 50% is due to environmental factors, with prolonged exposure to loud noise being the leading cause. One of the main challenges in hearing research is finding a pharmacotherapeutic strategy to prevent damage from noisy environments when they cannot be avoided. Recent studies have identified the α9α10 nicotinic cholinergic receptor in the sensory hair cells of the cochlea as a therapeutic target for developing drugs that enhance the olivocochlear efferent system to prevent acoustic trauma. This work aims to test potential positive allosteric modulators (PAMs) of α9α10 for their ability to prevent hearing loss due to noise exposure. Several candidates, including PAMs and agonists of receptors related to α9α10, such as α7, α4β2, α4β4, and serotonin receptors, were tested on recombinant α9α10 receptors expressed in Xenopus laevis oocytes. So far, chlorophenyl biguanide (a selective serotonin receptor agonist) showed some effect (133.1 ± 11.5% current amplitude normalized to 10 µM control ACh), but the other compounds, including ivermectin, TQS, 4BP-TQS, B-973B, A-867744 (PAMs of α7 nAChRs), NS-9283 (an α4β2 nAChR PAM), and LY-2087101 (a PAM of α7, α4β2, and α4β4 nAChRs), did not behave as PAMs of the α9α10 nAChR, with some even acting as blockers at high concentrations such as TQS, 4BP-TQS and B-973B.