Effects of glutamate

Hundt W, Holter SM, Spanagel R Discriminative stimulus effects of glutamate release inhibitors in rats trained to discriminate ethanol. Pharmacol Biochem Behav 59 691-695, 1998... 

Bondar, R. J. L. and Moss, G. A. Enhancing effect of glutamate on apparent serum Y glutamyl transpeptidase activity. Clin. Chem. (1974), 20, 317-319. 

Figure 17.5 Possible scheme for the initiation of depolarisation block of DA neurons. In (a) the excitatory effect of glutamate released on to the DA neuron from the afferent input is counteracted by the inhibitory effect of DA, presumed to be released from dendrites, acting on D2 autoreceptors. In the absence of such inhibition due to the presence of a typical neuroleptic (b) the neuron will fire more frequently and eventually become depolarised. At5q)ical neuroleptics, like clozapine, will be less likely to produce the depolarisation of A9 neurons because they are generally weaker D2 antagonists and so will reduce the DA inhibition much less allowing it to counteract the excitatory input. Additionally some of them have antimuscarinic activity and will block the excitatory effect of ACh released from intrinsic neurons (see Fig. 17.7)...

During ischaemia, NOS is activated by calcium influx or by cytokines like tumour necrosis factor (TNF) or by lipopolysaccharide (LPS) and NO is produced in excess. It has been proposed that the excitotoxic effect of glutamate, which contributes to ischaemia-induced neuronal damage, is mediated by increased production of NO via a chain of events that includes increases in intracellular calcium (via glutamate activation of NMDA receptors), calcium activation of NOS, production of NO and peroxynitrite, and induction of lipid peroxidation. In fact, N-nitro-L-atginine, a selective inhibitor of NOS, has been shown to prevent glutamate-induced neurotoxicity in cortical cell cultures (Dawson rf /., 1991). 

Cape, E. G. Jones, B. E. (2000). Effects of glutamate agonist versus procaine... 

PROTEINS OF THE POSTSYNAPTIC DENSITY MEDIATE INTRACELLULAR EFFECTS OF GLUTAMATE RECEPTOR ACTIVATION 284... 

While all of these events are interconnected, the two most critical are neuronal rapid influx of Ca2+ and activation of nNOS, both which trigger all downstream events. Therefore, directly blocking the toxic effects of glutamate /NO, can be achieved through many means, including selective nNOS inhibitors, Ca2+ channel blockers [NMDA, Kainate/AMPA] [ryanodine-sensitive, IP3], calmodulin antagonists, Ca2+... 

The subject of the effect of glutamic acid on "intelligence," as well as many related problems, needs to be investigated fully, bearing in mind the considerations we have presented here. 

In addition to epilepsy, neuronal death due to the toxic effects of glutamate has also been implicated in cerebral ischaemia associated with multi-infarct dementia and possibly Alzheimer s disease. With the plethora of selective excitatory amino acid receptor antagonists currently undergoing development, some of which are already in clinical trials, one may expect definite advances in the drug treatment of neurodegenerative disorders in the near future. 

The efficacy of barbiturates as antiepileptic drugs can be attributed to their effect on the stimulation of epileptogenic neurons, and also on the GABA-ergic channel in the CNS by elevating of the inhibitory action of GABA. Furthermore, barbiturates can reduce the excitatory effects of glutamate at synapses. It is not presently known which of these proposed mechanisms is more important for the development of antiepileptic activity. 

Mechanism of Action A neurotransmitter inhibitor that decreases the effects of glutamate, the principal excitatory neurotransmitter in the brain. Persistent CNS excitation by glutamate is thought to cause the symptoms of Alzheimer s disease. Therapeutic Effect May reduce clinical deterioration in moderate to severe Alzheimer s... 

P-Amyloid protein increases toxic effects of glutamate in neuron cell growth. 

Table 5.1 Stimulatory effect of glutamate-mediated Ca2+ influx on enzymic activities involved in excitotoxicity...

Fig. 5.2 Effect of glutamate (a) and NMDA (b) on the CPLA2 activity of neuron-enriched cultures from rat cerebral cortex. CPLA2 specific activity is expressed as pmol/min/mg protein...

Fig. 5.4 Effects of glutamate on diacylglycerol lipase and monoacylglycerol lipase activities of neuron-enriched cultures from fetal mouse spinal cord. Diacylglycerol lipase (clear bars) and monoacylglycerol glycerol lipase (hatched bars). Data modified from Farooqui et al., 1993...

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