Attenuation of noise-induced hearing loss using methylene blue

Hearing impairment is a rapidly growing healthcare issue worldwide, which has a profound impact on an individual's quality of life. Noise exposure is one of the major causes of sensorineural hearing loss, such as noise-induced hearing loss (NIHL), which is one of the most common occupational diseases in both developed and developing countries.1 Approximately 5% of the world's population suffers from hearing loss due to exposure to high levels of noise.2 Hence, a significant effort has been made to understand the pathophysiological mechanisms of noise-induced cell death in the cochlea as well as to develop interventions in order to reduce or prevent NIHL. The current prevention method of NIHL is to wear hearing-protection devices (HPD). However, HPD may provide inadequate protection, and further, there may be poor compliance in the use of HPD primarily due to impaired communication.3 Therefore, strategies are being continuously developed for the prevention of NIHL through the utilization of pharmacological agents. Accumulating evidence indicates that noise induces intense metabolic activity, which is the primary cause of intense mitochondrial oxidative phosphorylation and resultant reactive oxygen species (ROS) overproduction, overwhelming endogenous antioxidant defenses.4 The overproduction of ROS could also trigger reactive nitrogen species (RNS) formation in the mitochondria.5 The overproduced ROS and RNS after exposure to high levels of noise have been known to be the major contributors to NIHL. In addition, ischemia/reperfusion injury caused by an alteration of blood flow in the cochlea, glutamate excitotoxicity of auditory nerves caused by an excess release of glutamate in the inner hair cells (IHC) and calcium overload in the outer hair cells (OHC) in response to intense noise have been reported to have important roles in the pathological mechanism of NIHL.6 Accordingly, many researchers have made efforts to develop therapeutic agents against them.6 In particular, pharmacological intervention-targeted oxidative stress using various antioxidants, such as N-acetyl cysteine, D-methionine and resveratrol, have shown beneficial effects against NIHL in animal model systems.7 Moreover, clinical trials of these antioxidants are in progress.8 However, the efficacy of these antioxidants may be limited,6 indicating that the combinations of agents with different mechanisms of action having additive effects need to be developed. Methylene blue (3,7-bis(dimethylamino) phenazathionium chloride; MB), which was first synthesized as an aniline-based dye, has been used for a wide range of indications, such as methemoglobinemia, malaria, hypotension in septic shock and cyanide poisoning.9 It has also been utilized as a photosensitizer for cancer treatment and for treating infections.10 The biological effects of MB are closely associated with its redox characteristics. Because of its low redox potential, MB is efficient in cycling between the oxidized and reduced forms under the presence of proper redox centers, such as those in the mitochondria.9 Based on the redox property of MB, it can prevent electron leakage, increase mitochondrial oxidative phosphorylation and reduce ROS overproduction under pathological conditions, thus demonstrating that MB exhibits antioxidant effects. In addition, MB has been shown to have neuroprotective effects in multiple animal models of neurodegenerative diseases, including Alzheimer's disease and Huntington's disease.11, 12 MB also has the potential to prevent structural and functional neural damage13, therefore implying that MB can be a new promising drug for the treatment of various ROS-related diseases. Thus, in the present study, we explored the possibility of whether MB can prevent noise-induced cochlear injury as well as the molecular mechanisms of how MB protects NIHL using the in vitro UB-OC1 cell system and in vivo animal model system based on the antioxidant and neuroprotective effects of MB.