Ototoxicity: Understanding Oxidative Mechanisms

Abstract

O totoxicity and otoprotection present exciting new opportunities for audiologic practice and research. Through understanding the underlying mechanisms of ototoxic hearing loss, we have the very real possibility of developing new drugs in the near future that either do not have ototoxicity as a side effect or work specifically to prevent ototoxicity as a side effect of other drugs. The mechanisms of ototoxic damage and protection can be complex but some general concepts apply.In virtually all scientific journals and even in the popular press, we read about "oxidative damage" and "oxidative stress" as a factor in many degenerative processes. Although oxidative processes are part of normal metabolic activity, they also playa major role in many disease processes and in aging. Oxidative damage is also a common factor in cisplatin-induced, aminoglycoside-induced, and noise-induced hearing loss. Therefore audiologists and others working in hearing loss prevention should have a working knowledge of oxidative mechanisms. The following is a list of terms and concepts that may be helpful in reading the articles on ototoxicity in this issue of JAAA. BASIC CONCEPTS OF OXIDATIVE PROCESSESOxidize: To oxidize a compound means to add oxygen to the compound, to remove hydrogen from a compound (dehydrogenate it), or to remove electrons from another molecule or atom. An "oxidant" or "oxidizer" generally removes electrons from another compound. Reduce:To reduce a compound means to remove oxygen from a compound, to add hydrogen to a compound, or to donate one or more electrons from a compound. A "reducing agent" usually means an agent that donates electrons. (The substance that is oxidized is the reducing agent. The substance that is reduced is the oxidizing agent.) Free Radicals: Free radicals are molecules that can exist independently and have at least one unpaired electron. The unpaired electron causes the molecule to be energetically unstable and thus highly reactive and transient. To stabilize, the free radical must take an electron from another molecule to complete its electron pair. Taking an electron from the other molecule is called "oxidizing" the other molecule. Through this process, the first molecule is now stable, but the second molecule has become a free radical, and the process can continue to other molecules.Redox Reactions: When a free radical oxidizes an adjacent molecule and that adjacent molecule then becomes a free radical, a chain reaction along a series of molecules can occur. These chain reactions of electron transfers are called redox reactions.

The use of zebrafish for assessing ototoxic and otoprotective agents

“…Direct intraperitoneal injection of GSH ester but not GSH has been shown to reduce cisplatin-induced ototoxicity in a rat model (Campbell, 2003). This diVerence in activity may be attributable to more eVective transport of GSH ester into cells where it is converted to intracellular GSH (Anderson et al, 1990).…”

“…Oxidative stress in auditory sensory cells is caused by loss of neurotrophic factors, ischemia-reperfusion and ototoxins, which can occur in adults in response to aging (presbyacusis), disease, acoustic stimulation, injury and treatment with ototoxic drugs (Campbell, 2003). The loss of neurotrophic factors and ototoxins initiates the production of intracellular oxygen species and free radicals (Miller et al, 2002).…”

“…Morphometric analysis was then used to quantify Xuorescence intensity of hair cells. Cisplatin has been routinely used as an ototoxicity inducer in mammalian models for screening potential otoprotectants (Plaxe et al, 1994;Bohm et al, 1999;Peters et al, 2000;Rybak et al, 2000;Campbell, 2003). Fluorescence intensity was quantiWed using particle analysis (NIH Image); background staining was signiWcantly reduced by establishing background threshold levels and restricting particle size to include only the area surrounding the neuromasts (see Section 2).…”

Comparison of the effects of N-acetyl-cysteine and ginseng in prevention of noise induced hearing loss in male textile workers

“…Accumulation of ROS causes failure in antioxidant's action in neutralizing free radicals; consequently inner hair cells (IHCs) and largely outer hair cells (OHCs) cellular lipids, proteins and DNA damage and cells die through either apoptosis (programmed cell death) or necrosis. [15][16][17] As antioxidants scavenge and remove ROS and the other free oxygen radicals, they can prevent cells from dangerous materials. Two ways exist to increase antioxidant levels: Endogenous way (using sound conditioning) and exogenous way (direct infusion into the cochlea or systematic infusion into the whole body).…”

Epicatechin protects auditory cells against cisplatin-induced death

“…Accordingly, free radical production with resulting glutathione depletion and subsequent lipid peroxidation is a proposed mechanism for cisplatin ototoxicity [12]. Many agents have been tested to ameliorate cisplatin-induced ototoxicity including fosfomycin [13], sodium thiosulfate, D-methionine [8], L-methionine [14], diethyldithiocarbamate [12], lipoic acid [15], L-N-acetylcysteine [16], glutathione ester [17], and sodium salicylate [11].…”