Membrane permeability of redox active metal chelators: An important element in reducing hydroxyl radical induced NAD+ depletion in neuronal cells

There is substantial evidence implicating increased production of the hydroxyl radical and oxidative stress in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Significant amounts of hydroxyl radicals will be produced in the presence of hydrogen peroxide and redox active iron via Fenton chemistry. Increased iron levels within the cytoplasm of vulnerable neurons suggest that this may also be an important site of oxidative activity. We investigated the likelihood that intracellular, rather than extracellular chelation of ferrous or ferric iron may be more effective in reducing hydroxyl radical induced cell damage and preserving NAD+ levels and cell viability. Using intracellular NAD(H) measurements as an indicator of cell viability we found that membrane permeable ferrous chelators were most efficient in preserving cellular NAD+ levels. Hydrophilic, ferrous or ferric chelators and lipophilic ferric chelators were essentially ineffective in preventing cellular NAD+ depletion when added at physiological concentrations. We propose that lipophilic ferrous chelators, due to their actions inside the cell, are effective agents for moderating neuronal damage in conditions such as AD where intracellular oxidative stress plays a significant role in disease pathology.