Neurotoxicity of reactive aldehydes: The concept of “aldehyde load” as demonstrated by neuroprotection with hydroxylamines

Niemann-Pick C1 Functions in Regulating Lysosomal Amine Content

“…3-AP is formed endogenously from the metabolism of spermidine to putrescine by the enzyme polyamine oxidase. This compound was selected because it has been shown to be specifically toxic to lysosomes through its ability to facilitate membrane rupture, and there have been numerous reports on its neurotoxic effects (48,49). Consistent with the NPC disease pathology, 3-AP has been shown to be particularly toxic to neuronal cells relative to other cells for unknown reasons (50).…”

Phenelzine: An Old Drug That May Hold Clues to The Development of New Neuroprotective Agents

“…GABAergic agents, including tiagabine and vigabatrin (gamma-vinyl GABA), have been reported in preclinical studies to reduce the extent of ischemiamediated neuronal damage in vivo and in vitro (40,46,47), and thus it is not surprising that PLZ has been shown to reduce neuronal damage in an animal model of ischemia (8). It is also interesting to note that glutamate-associated excitotoxicity is also thought to play a role in the neurodegeneration observed in Alzheimer's disease (48)(49)(50) and GABAergic deficits have been reported in AD, although these latter findings are conflicting and complicated by variables such as illness severity and postmortem handling of brain tissue (51).…”

“…Theoretically, antioxidants counteract the actions of ROS and therefore reduce lipid peroxidation and the generation of the resultant aldehyde byproducts, but antioxidants have not been particularly effective in preventing aldehyde-mediated cytotoxicity either in animal models (8) or clinically (64). An effective alternative method for reducing aldehyde-mediated toxicity is "sequestering" through direct chemical interaction with the aldehyde, producing non-reactive and non-toxic products, thus reducing the reactive "aldehyde load.…”

“…It has also been reported to reduce neuronal loss in a gerbil model of transient forebrain ischemia (8).…”

The Biochemical Basis of Autistic Behavior and Pathology

“…The reactive oxygen species (ROS) generated by oxidative stress is a cause of lipid peroxidation, which has been reported to be increased in serum and urine from autistic children [14,15]. Lipid peroxidation is a well established cause of reactive aldehyde generation, which plays a key role in apoptotic mechanisms leading to both neuronal and glial cell death [140]. Damaged cells further stimulate microglial activation, which also contributes to free radical production [141].…”