Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

INTRODUCTION
Oxidative stress
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Oxygen is necessary for life, but paradoxically, it is also toxic as a by-product of
its metabolism produces ROS (Reaction 1). ROS are defined as molecular entities that
react with cellular components, resulting in detrimental effects on their function as they
are highly toxic to cells. ROS include both molecular species, such as hydrogen
peroxide (H2O2), and free radicals (a term used to designate any chemical species
containing highly reactive unpaired electrons), such as superoxide anion (O2 ●─ ), and
hydroxyl radical ( ● OH). The latter is the most potentially dangerous of ROS, short-lived
but highly reactive, which causes enormous damage to biological molecules. In addition
to ROS, reactive nitrogen species (RNS) are also generated notably nitric oxide (NO ● ,
NO) and peroxynitrite (ONOO ●─ ).
Reaction 1: Metabolism of O2 and production of ROS
O2 + e ─ ●─ ─ +
→ O2 + e + 2H → H2O2 + e ─ → ● OH + OH ─ + e ─ + 2H + → 2H2O
ROS can interact with nearby critical cellular components such as membrane
lipids, proteins, and DNA and oxidize them, leading to a wide range of damaging
effects. In the case of proteins, ROS may directly oxidize amino acids leading to loss of
functions of proteins and disruption of the active sites of enzymes. Exposure of
membranes of fatty acids to ROS may result in the formation of alkoxyl (RO ● ), peroxyl
(ROO ● ), and lipid epoxides and hydroperoxides (ROOH). The latter can additionally be
further oxidized close by unsaturated fatty acids in a chain reaction event stimulated by
ROO ● and RO ● , leading to disruption of both plasma and mitochondrial membranes.
Oxidation of nucleic acids may provoke strand breakage, nucleic acid-protein
crosslinking, and nucleic base modifications which can have an effect on DNA
transcription, translation and replication. Within neurons ROS may also interfere with
signal transduction and gene expression affecting cell survival, thus inducing cell death.