Cell death mechanisms in the early stages of acute glutamate neurotoxicity.

The present study focused on the early stages of acute glutamate (L-Glu)-induced neurotoxic mechanisms, both biochemical, e.g. intracellular reactive oxygen species (ROS) and associated parameters as well as gene expression of cell survival/death pathways, i.e. Bcl-2 and caspases. Stereotactic intracortical injections of L-Glu (1micromol/1microl) resulted in decreased size of pyramidal neurons in rat after 1h. We also observed that intracellular ROS, calcium (Ca(2+)) and peroxynitrite (ONOO(-)) production were significantly elevated, whereas, mitochondrial transmembrane potential (DeltaPsim) and total glutathione were significantly decreased by L-Glu bolus. The Bcl-2/Bax ratio in the L-Glu-injected rats was found to be significantly lower than the controls. Moreover, acute L-Glu significantly induced mRNA expression of nNOS, iNOS, caspase-3 and caspase-9. It may be concluded from the present study that acute L-Glu administration, at an early stage, increases intracellular ROS accumulation, Ca(2+) levels and peroxynitrite production and decreases glutathione pool. Furthermore, it appears that decreased mitochondrial Bcl-2/Bax ratio might have upregulated the mRNA expression of caspase-3 and caspase-9 which launch cell death cascade. Regarding the chronology of the events, we presume that acute L-Glu increases ROS and decreases DeltaPsim and glutathione rapidly and it is more likely that these events precede gene expression changes, ultimately resulting in neuronal damage/death.