Assessment of Nutrient Supplement to Reduce Gentamicin-Induced Ototoxicity

Abstract

Gentamicin is an aminoglycoside antibiotic used to treat gram-negative bacterial infections. Treatment with this antibiotic carries the potential for adverse side effects, including ototoxicity and nephrotoxicity. Ototoxic effects are at least in part a consequence of oxidative stress, and various antioxidants have been used to attenuate gentamicin-induced hair cell death and hearing loss. Here, a combination of nutrients previously shown to reduce oxidative stress in the hair cells and attenuate hearing loss after other insults was evaluated for potential protection against gentamicin-induced ototoxicity. Guinea pigs were maintained on a nutritionally complete standard laboratory animal diet or a diet supplemented with β-carotene, vitamins C and E, and magnesium. Three diets with iterative increases in nutrient levels were screened; the final diet selected for study use was one that produced statistically reliable increases in plasma levels of vitamins C and E and magnesium. In two separate studies, significant decreases in gentamicin-induced hearing loss at frequencies including 12 kHz and below were observed, with less benefit at the higher frequencies. Consistent with the functional protection, robust protection of both the inner and outer hair cell populations was observed, with protection largely in the upper half of the cochlea. Protection was independently assessed in two different laboratories, using two different strains of guinea pigs. Additional in vitro tests did not reveal any decrease in antimicrobial activity with nutrient additives. Currently, there are no FDA-approved treatments for the prevention of gentamicin-induced ototoxicity. The current data provide a rationale for continued investigations regarding translation to human patients.

Aminoglycoside-Induced Oxidative Stress: Pathways and Protection

“…Signifi cant decreases in gentamicin-induced hearing loss at 12 kHz and below were reported, with protection of both inner and outer hair cells. These fi ndings provide a rationale for future studies in patients (Le Prell et al 2014 ).…”

“…D -methionine afforded protection in animal studies without affecting gentamicin serum levels (Sha and Schacht 2000 ). For a current review of gentamicin otoprotection, see Le Prell et al ( 2014 ).…”

Antioxidants and Their Effect on Stress-Induced Pathology in the Inner Ear

“…These include vitamin E, D -methionine, α-lipoic acid, and ebselen (Takumida et al 1999 ;Sha and Schacht 2000 ;Fetoni et al 2003 ). Promising results were also recently reported for a combination of antioxidants including several vitamins and magnesium (Le Prell et al 2014 ). In addition, iron chelators like deferoxamine have also been used with modest success (Dehne et al 2002 ).…”

“…In addition, iron chelators like deferoxamine have also been used with modest success (Dehne et al 2002 ). More exotic ideas have also been tested, again with varying success, and these include modulating the role of NF-κB in the apoptotic cascade by using salicylate and 2,3-dihydroxybenzoate (Jiang et al 2005 ), as well as an emerging report on nutrient supplementation in gentamicin ototoxicity (Le Prell et al 2014 ). Polony and colleagues have found promising results with rasagiline (a selective monoamine oxidase type B inhibitor used in early Parkinson's disease therapy) in aminoglycoside toxicity.…”

Cellular Mechanisms of Age-Related Hearing Loss

“…Mg ++ has been demonstrated to increase inner ear blood fl ow (Scheibe et al 2000 ;Haupt and Scheibe 2002 ), and its effi cacy in attenuating NIHL has been demonstrated (Sendowski 2006 ). The ACEMg treatment was administered to guinea pigs (Le Prell et al 2007 ) and CBA/J mice (Le Prell et al 2011 ) showing reduced permanent threshold shifts after NIHL and also reduced threshold shift after gentamicin ototoxicity (Le Prell et al 2014 ). Studies in humans indicate that regular dietary intake of antioxidants correlates with lower risks of hearing loss (Durga et al 2007 ;Shargorodsky et al 2010 ;Choi et al 2014 ).…”