8-hydroxyguanine and Hearing-Loss--Noise-Induced

This review is based on the honor of receiving the Discovery Award from the Society of Free Radical Biology and Medicine. The review is reflective and presents our thinking that led to experiments that yielded novel observations. Critical questioning of our understanding of oxygen free radicals in biomedical problems led us to use and develop more direct and extremely sensitive methods. This included nitrone free radical spin trapping and HPLC-electrochemical detection. This technology led to the pioneering use of salicylate to trap hydroxyl free radicals and show increased flux in ischemia/reperfused brain regions and also to first sensitively detect 8-hydroxyl-2-deoxyguanosine in oxidatively damaged DNA and help assess its role in cancer development. We demonstrated that methylene blue (MB) photoinduces formation of 8-hydroxyguanine in DNA and RNA and discovered that MB sensitively photoinactivates RNA viruses, including HIV and the West Nile virus. Studies in experimental stroke led us serendipitously to discover that alpha-phenyl-tert-butylnitrone (PBN) was neuroprotective if given after the stroke. This led to extensive commercial development of NXY-059, a PBN derivative, for the treatment of stroke. More recently we discovered that PBN nitrones have potent anti-cancer activity and are active in preventing hearing loss caused by acute acoustical trauma.

Topics: Animals; Benzenesulfonates; Brain Neoplasms; Cyclic N-Oxides; DNA Damage; Guanine; Hearing Loss, Noise-Induced; HIV-1; Humans; Methylene Blue; Phototherapy; Reactive Oxygen Species; RNA Virus Infections; Stroke; West Nile virus

Evaluating the correlation between otoacoustic emission levels, styrene exposure, and oxidative stress biomarkers concentration in styrene-exposed subjects, to investigate the role of oxidative stress in outer hair cell damage.. Distortion product otoacoustic emissions were measured in the exposed workers and in a control group. Separation between the distortion and reflection otoacoustic components was performed by time-frequency-domain filtering. The urinary concentration of the DNA and RNA oxidation products, namely 8-oxo-7,8-dihydroguanine (oxoGua), 8-oxo-7,8-dihydro-2'-deoxyguanosine (oxodGuo), and 8-oxo-7,8-dihydroguanosine (oxoGuo), were evaluated.. Nine subjects exposed to styrene in a fiberglass factory, eight control subjects. The two groups were statistically equivalent in mean age.. Statistically significant differences were found in the distortion component levels between the exposed and the control group. High levels of the oxidative damage biomarkers were found in the workers exposed to high levels of styrene. Significant negative correlation was found between the otoacoustic emission distortion component levels and the concentration of the oxoGuo biomarker.. Exposure-induced damage of the cochlear amplifier is shown in the mid-frequency range, confirming animal experiments, in which hair cells in the cochlear middle turn were damaged. Hearing damage is consistent with the outer hair cell apoptosis pathway associated with oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acoustics; Adult; Apoptosis; Biomarkers; Case-Control Studies; Deoxyguanosine; DNA Damage; Female; Guanine; Guanosine; Hair Cells, Auditory, Outer; Hearing Loss, Noise-Induced; Hearing Tests; Humans; Male; Middle Aged; Noise, Occupational; Occupational Diseases; Occupational Exposure; Occupational Health; Otoacoustic Emissions, Spontaneous; Oxidative Stress; Risk Factors; Styrene