Cell death mechanisms in the early stages of acute glutamate neurotoxicity

• Published in: Neuroscience research 2010-03, Vol.66 (3), p.271-278
• Main Authors: Kumar, Alok, Singh, Ram Lakhan, Babu, G. Nagesh
• Format: Article
• Language: English
• Subjects: Animals; Bcl-2 family; bcl-2-Associated X Protein - metabolism; Calcium - metabolism; Caspase 3 - metabolism; Caspase 9 - metabolism; Caspases; Cell Death - physiology; Cell Size; Cerebral Cortex - pathology; Cerebral Cortex - physiology; Glutamic Acid - metabolism; Glutamic Acid - toxicity; Glutathione - metabolism; GSH; Male; Membrane Potential, Mitochondrial - physiology; Nitric oxide synthase; Nitric Oxide Synthase Type I - metabolism; Nitric Oxide Synthase Type II - metabolism; Peroxynitrite; Peroxynitrous Acid - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyramidal Cells - physiology; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; RNA, Messenger - metabolism; ROS
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2009.11.009

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 (1 μmol/1 μl) resulted in decreased size of pyramidal neurons in rat after 1 h. We also observed that intracellular ROS, calcium (Ca 2+) and peroxynitrite (ONOO −) production were significantly elevated, whereas, mitochondrial transmembrane potential (ΔΨm) 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 ΔΨm and glutathione rapidly and it is more likely that these events precede gene expression changes, ultimately resulting in neuronal damage/death.