Changes in ATP content in cerebellar granule cells during hyperstimulation of glutamate receptors: Possible role of NO and nitrite ions

Abstract

In primary 7-8-day culture of cerebellar granule cells, glutamate exposure (100 microM, 10-240 min) induced a 60-30% drop in ATP level; during the postglutamate period ATP level completely recovered after 24 h. Inhibition of NO-synthase with L-NAME during glutamate application resulted in less pronounced decrease in ATP level immediately after its application and had no effect on ATP recovery after 24 h. It was found that hyperstimulation of glutamate receptors elevates concentration of NO products (nitrites and nitrates), while NO2(-) ions can increase ATP content.

Effects of Selective Inhibitors of Neuronal and Inducible NO-Synthase on ATP Content and Survival of Cultured Rat Cerebellar Neurons during Hyperstimulation of Glutamate Receptors

“…Nonspecifi c inhibition of NO synthesis with L-NAME prevented ATP drop by only 10%, which is consistent with our previous data [3] and is in accordance with the data on cortical neurons [4]. Specifi c inhibition of NO-synthase ensured better protection of cells from ATP drop: iNOS inhibitor increased ATP level by 14% and nNOS inhibitor by 22% in comparison with the effect of Glu (p<0.05; Fig.…”

“…Under these conditions, inhibition of NO synthesis is not suffi cient to fully ensure the survival of neurons under the action of Glu. Moreover, washout after 30-min application of Glu does not restore ATP level in "old" neurons, in contrast to "young" ones that showed signifi cant recovery of ATP content within 24 h [3].…”

“…Impaired metabolism of the major excitatory CNS neurotransmitter glutamate (Glu) followed by a sharp increase in its content in the synaptic clefts is the trigger for the development of neuronal damage in a variety of neurological diseases including stroke, epilepsy, Parkinson's disease, Alzheimer's disease, and traumatic brain injury [7]. All these diseases are usually accompanied by hypoxia/ischemia of the nerve tissue and enhanced NO formation in the brain [1,15].The progress in the study of the toxic effects of Glu is largely due to discovery of the role of mitochondrial dysfunction in the process leading to the decrease in intracellular ATP concentration in neurons [2,3]. It was shown that the effect of different NOdonors on hippocampal cell cultures markedly reduces ATP levels [6].…”

“…In ischemia and trauma, inducible NO-synthase (iNOS) of glial cells also contributes to NO production [5]. We have previously found that nonspecifi c inhibition of NO synthesis with L-NAME protects the culture of 7-8-dayold neurons from Glu-induced ATP drop [3]. Several studies have shown that selective inhibition of nNOS reduced neuronal damage during ischemia [12,14].…”

“…The progress in the study of the toxic effects of Glu is largely due to discovery of the role of mitochondrial dysfunction in the process leading to the decrease in intracellular ATP concentration in neurons [2,3]. It was shown that the effect of different NOdonors on hippocampal cell cultures markedly reduces ATP levels [6].…”