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.
Kumar
Alok
A
Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India.
Singh
Ram Lakhan
RL
Babu
G Nagesh
GN
D000818:Animals; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D048429:Cell Size; D002540:Cerebral Cortex / Q000473:pathology / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017966:Pyramidal Cells / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494828:Bax protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D030421:Peroxynitrous Acid; D018698:Glutamic Acid; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D005978:Glutathione; D002118:Calcium