Aberrant redox-sensitive reactions and accumulation of oxidative damage can impair body functions, contribute to the development of various pathologies and accelerate aging. Although antioxidant substances have long been recognized as a measure of alleviating oxidative stress and restoring redox balance, the arsenal of effective means of preventing the development of various diseases and premature aging is still limited. There is an emerging field that utilizes molecular hydrogen (H2) as a scavenger of free radicals and reactive oxygen species (ROS). Among the remarkable characteristics of H2 is its ability to counteract harmful effects of hydroxyl radical and peroxynitrite without affecting activity of functionally important ROS, such as hydrogen peroxide and nitric oxide. The beneficial effects of H2 have been documented in numerous clinical studies and studies on animal models and cell cultures. However, the established scavenging activity of H2 towards free radicals can only partially explain the beneficial effects of H2, because the effects are achieved at very low concentrations of H2. Given the rate of H2 diffusion, such low concentrations may not be sufficient to scavenge continuously generated free radicals. Recent data suggest that molecular H2 can also act as a signaling molecule and induce defense responses. However, the exact targets and mechanism(s) by which H2 exerts these effects are unknown, nor is it known whether the regulation of signaling pathways is performed directly by H2 or whether there is an intermediate trigger(s) or catalyst(s) sensitive to modifications by H2. Using Drosophila, we recently demonstrated the ability of orally administered H2 to negate the severe physiological defects in mutants with impaired redox and mitochondrial dysfunction caused by knock-down of the redox-sensing and regulating enzymes, peroxiredoxins (Prx). The most noticeable effect of hydrogen was on the locomotor ability of mitochondrial Prx mutants. We also found that underexpression of mitochondrial Prxs by a motor neuron-specific driver was critical for the life span of the flies, suggesting that H2 may be particularly beneficial for maintaining proper motor neuronal and/or neuromuscular function and longevity by modulating the redox-sensitive pathways in these tissues. Thus the experimental approach will be i) to characterize the state of redox and oxidative damage in flies with reduced levels of mitochondrial peroxiredoxins using a battery of biochemical tests to elucidate the sparing effects of H2 on redox crisis; and ii) to study the effects of hydrogen in Drosophila model of amyotrophic lateral sclerosis disease, associated with motor neuron dysfunction.
Arsenal of means to reduce age-related degenerative processes is still limited. Growing evidence has demonstrated that exogenously applied hydrogen gas can have a significant therapeutic effect. The proposed study will elucidate the mechanisms of action of hydrogen and determine its role in preventing the development of neurological disorders, including Lou Gehrig's disease.
