Abstract
Despite causing permanent hearing loss by damaging inner ear sensory cells, aminoglycosides (AGs) remain one of the most widely used classes of antibiotics in the world. Although the mechanisms of cochlear sensory cell damage are not fully known, reactive oxygen species (ROS) are clearly implicated. Mitochondrial-specific ROS formation was evaluated in acutely cultured murine cochlear explants exposed to gentamicin (GM), a representative ototoxic AG antibiotic. Superoxide (O 2 ·-) and hydrogen peroxide (H 2 O 2) were measured using MitoSOX Red and Dihydrorhodamine 123, respectively, in sensory and supporting cells. A 1-h GM exposure significantly increased O 2 ·-formation in IHCs and increased H 2 O 2 formation in all cell types. At the same time point, GM significantly increased manganese superoxide dismutase (MnSOD) levels while significantly decreasing copper/zinc superoxide dismutase (CuZnSOD) in cochlear sensory cells. This suggests (1) a rapid conversion of highly reactive O 2 ·-to H 2 O 2 during the acute stage of ototoxic antibiotic exposure and (2) that the endogenous antioxidant system is significantly altered by AGs. Fluorescence intensity-based measurements of reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] and mitochondrial membrane potential were measured to determine if increases in GM-induced ROS production were correlated with changes in mitochondrial metabolism. This project provides a basis for understanding the mechanisms of mitochondrial ROS production in cochlear cells exposed to ototoxic antibiotics. Understanding the nature of ototoxic antibiotic-induced changes in mitochondrial metabolism is critical for developing hearing loss treatment and prevention strategies.
| Original language | English (US) |
|---|---|
| Article number | 051403 |
| Journal | Journal of Biomedical Optics |
| Volume | 24 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2019 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Electronic, Optical and Magnetic Materials
- Biomaterials
- Atomic and Molecular Physics, and Optics
- Biomedical Engineering
Cite this
Aminoglycosides rapidly inhibit NAD(P)H metabolism increasing reactive oxygen species and cochlear cell demise. / Desa, Danielle E.; Nichols, Michael G.; Smith, Heather Jensen.
In: Journal of Biomedical Optics, Vol. 24, No. 5, 051403, 01.05.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Aminoglycosides rapidly inhibit NAD(P)H metabolism increasing reactive oxygen species and cochlear cell demise
AU - Desa, Danielle E.
AU - Nichols, Michael G.
AU - Smith, Heather Jensen
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Despite causing permanent hearing loss by damaging inner ear sensory cells, aminoglycosides (AGs) remain one of the most widely used classes of antibiotics in the world. Although the mechanisms of cochlear sensory cell damage are not fully known, reactive oxygen species (ROS) are clearly implicated. Mitochondrial-specific ROS formation was evaluated in acutely cultured murine cochlear explants exposed to gentamicin (GM), a representative ototoxic AG antibiotic. Superoxide (O 2 ·-) and hydrogen peroxide (H 2 O 2) were measured using MitoSOX Red and Dihydrorhodamine 123, respectively, in sensory and supporting cells. A 1-h GM exposure significantly increased O 2 ·-formation in IHCs and increased H 2 O 2 formation in all cell types. At the same time point, GM significantly increased manganese superoxide dismutase (MnSOD) levels while significantly decreasing copper/zinc superoxide dismutase (CuZnSOD) in cochlear sensory cells. This suggests (1) a rapid conversion of highly reactive O 2 ·-to H 2 O 2 during the acute stage of ototoxic antibiotic exposure and (2) that the endogenous antioxidant system is significantly altered by AGs. Fluorescence intensity-based measurements of reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] and mitochondrial membrane potential were measured to determine if increases in GM-induced ROS production were correlated with changes in mitochondrial metabolism. This project provides a basis for understanding the mechanisms of mitochondrial ROS production in cochlear cells exposed to ototoxic antibiotics. Understanding the nature of ototoxic antibiotic-induced changes in mitochondrial metabolism is critical for developing hearing loss treatment and prevention strategies.
AB - Despite causing permanent hearing loss by damaging inner ear sensory cells, aminoglycosides (AGs) remain one of the most widely used classes of antibiotics in the world. Although the mechanisms of cochlear sensory cell damage are not fully known, reactive oxygen species (ROS) are clearly implicated. Mitochondrial-specific ROS formation was evaluated in acutely cultured murine cochlear explants exposed to gentamicin (GM), a representative ototoxic AG antibiotic. Superoxide (O 2 ·-) and hydrogen peroxide (H 2 O 2) were measured using MitoSOX Red and Dihydrorhodamine 123, respectively, in sensory and supporting cells. A 1-h GM exposure significantly increased O 2 ·-formation in IHCs and increased H 2 O 2 formation in all cell types. At the same time point, GM significantly increased manganese superoxide dismutase (MnSOD) levels while significantly decreasing copper/zinc superoxide dismutase (CuZnSOD) in cochlear sensory cells. This suggests (1) a rapid conversion of highly reactive O 2 ·-to H 2 O 2 during the acute stage of ototoxic antibiotic exposure and (2) that the endogenous antioxidant system is significantly altered by AGs. Fluorescence intensity-based measurements of reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] and mitochondrial membrane potential were measured to determine if increases in GM-induced ROS production were correlated with changes in mitochondrial metabolism. This project provides a basis for understanding the mechanisms of mitochondrial ROS production in cochlear cells exposed to ototoxic antibiotics. Understanding the nature of ototoxic antibiotic-induced changes in mitochondrial metabolism is critical for developing hearing loss treatment and prevention strategies.
UR - http://www.scopus.com/inward/record.url?scp=85056420773&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056420773&partnerID=8YFLogxK
U2 - 10.1117/1.JBO.24.5.051403
DO - 10.1117/1.JBO.24.5.051403
M3 - Article
VL - 24
JO - Journal of Biomedical Optics
JF - Journal of Biomedical Optics
SN - 1083-3668
IS - 5
M1 - 051403
ER -