Iodoacetate protects hippocampal neurons against excitotoxic and oxidativeinjury: involvement of heat-shock proteins and Bcl-2

Mild metabolic stress may increase resistance of neurons in the brain to su bsequent, more severe insults, as demonstrated by the ability of ischemic p re-conditioning and dietary restriction to protect neurons in experimental models of stroke- and age-related neurodegenerative disorders. In the prese nt study we employed iodoacetic acid (IAA), an inhibitor of glyceraldehyde- 3-phosphate dehydrogenase, to test the hypothesis that inhibition of glycol ysis can protect neurons. Pre-treatment of cultured hippocampal neurons wit h IAA can protect them against cell death induced by glutamate, iron and tr ophic factor withdrawal. Surprisingly, protection occurred with concentrati ons of IAA (2-200 nm) much lower than those required to inhibit glycolysis. Pre-treatment with IAA results in suppression of oxyradical production and stabilization of mitochondrial function in neurons after exposure to oxida tive insults. Levels of the stress heat-shock proteins HSP70 and HSP90, and of the anti-apoptotic protein Bcl-2, were increased in neurons exposed to IAA. Our data demonstrate that IAA can stimulate cytoprotective mechanisms within neurons, and suggest the possible use of IAA and related compounds i n the prevention and/or treatment of neurodegenerative conditions.