NOX3-TARGETED THERAPIES FOR INNER EAR PATHOLOGIES.
Inner ear pathologies are associated with major morbidity and loss of life quality in affected patients. In many of these conditions, production of reactive oxygen-species (ROS) is thought to be a key pathological mechanism. While the sources of ROS are complex (including for example mitochondria), there is increasing evidence that activation of NOX enzymes, in particular NOX3, plays a key role. NOX3 is a multi-subunit NADPH oxidase, functionally and structurally closely related to NOX1 and NOX2. In both the vestibular and the cochlear compartments of the inner ear, high levels of NOX3 mRNA are expressed. In NOX3 mutant mice, the vestibular function is perturbed due to a lack of otoconia, while only minor alterations of hearing have been documented. However, there is increasing evidence that activation of NOX3 through drugs, noise and probably also aging, leads to hearing loss. Thus, NOX3 is an interesting target to treat and prevent inner ear pathologies and a few first animal models based on drug - or molecular therapy have been reported. So far however, there are no specific NOX3 inhibitors with a documented penetration into the inner ear. Nevertheless, certain antioxidants and non-specific NOX inhibitors diminish hearing loss in animal models. Development of small molecules inhibitors or molecular strategies against NOX3 could improve specificity and efficiency of redox-targeted treatments. In this review, we will discuss arguments for the involvement of NOX3 in inner ear pathologies and therapeutic approaches to target NOX3 activity.
Department of Pathology and Immunology, Centre Médical Universitaire, 1, rue Michel-Servet CH-1211 Geneva 4, Switzerland. Francis.Rousset@unige.ch.
Francis
F
Rousset
Stephanie
S
Carnesecchi
Pascal
P
Senn
Karl-Heinz
KH
Krause
D000818:Animals; D006801:Humans; D007759:Labyrinth Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; D019255:NADPH Oxidases; C431570:Nox3 protein, human; C484511:Nox3 protein, mouse