The researchers discovered that when neurons in the brain experience oxidative stress - when the balance between the production of reactive oxygen species (free radicals) and antioxidant defences is thrown out of whack - GAPDH moves into the nucleus to increase protein turnover, and this then leads to cell death.
But when they tested the effects of salicylic acid on GAPDH, they watched as the two became bound together. This meant GAPDH could no longer pass into the nucleus of brain's neurons.
"The enzyme GAPDH, long thought to function solely in glucose metabolism, is now known to participate in intracellular signalling," said one of the team, Solomon Snyder from Johns Hopkins University. "The new study establishes that GAPDH is a target for salicylate drugs related to aspirin, and hence may be relevant to the therapeutic actions of such drugs."
The team is now continuing their investigation into the potential of salicylic acid as a wide-ranging treatment option.
The anti-Parkinson’s drug deprenyl has been shown to suppress nuclear translocation of HsGAPDH, an early step in cell death and the resulting cell death induced by the DNA alkylating agent N-methyl-N’-nitro-N-nitrosoguanidine. Here, we demonstrate that SA, which is the primary metabolite of aspirin (acetyl SA) and is likely responsible for many of its pharmacological effects, also suppresses nuclear translocation of HsGAPDH and cell death. Analysis of two synthetic SA derivatives and two classes of compounds from the Chinese medicinal herb Glycyrrhiza foetida (licorice), glycyrrhizin and the SA-derivatives amorfrutins, revealed that they not only appear to bind HsGAPDH more tightly than SA, but also exhibit a greater ability to suppress translocation of HsGAPDH to the nucleus and cell death.
Potentially therapeutic levels of SA for suppression of cell death are readily attainable since SA concentrations reaches ~140 μM (~20 mg/L) within 1 h following intake of 500 mg of aspirin . Furthermore, the discovery of SA derivatives, which are 3–30 times more efficacious than SA, further supports the possibility that salicylates may be of therapeutic value in the treatment or even prevention of several widespread and devastating neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases.