NMDA receptors neurotoxicity

Lipton SA, Sucher NJ, Kaiser PK, Dreyer EB (1991) Synergistic effects of HIV coat protein and NMDA receptor-mediated neurotoxicity. Neuron 7 111-118 Liu L, Callahan MK, Huang D, Ransohoff RM (2005) Chemokine receptor CXCR3 an unexpected enigma. Curr Top Dev Biol 68 149-181... 

O Donnell LA, Agrawal A, Jordan-Sciutto KL, Dichter MA, Lynch DR, Kolson DL (2006) Human immunodeficiency virus (HIV)-induced neurotoxicity roles for the NMDA receptor subtypes. J Neurosci 26 981-990... 

Interest in the PGs has recently reverted to their precursor arachidonic acid (AA), which seems to be able to act intracellulary as a second messenger, and also extra-cellularly. In this latter mode it may play a part in LTP. It is known that AA produces a long-lasting enhancement of synaptic transmission in the hippocampus that resembles LTP and in fact activation of NMDA receptors leads to the release of AA by phospholipase A2 (see Dumuis et al. 1988) and inhibition of this enzyme prevents the induction of LTP. AA has also been shown to block the uptake of glutamate (see Williams and Bliss 1989) which would potentiate its effects on NMDA receptors. This would not only prolong LTP but also cause neurotoxicity. 

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). 

NMDA receptor agonists derived from ibotenic acid. Preparation, neuroexcitation, and neurotoxicity. Eur J Pharmacoi. 189(6) 381-91. 

It should be noted that other types of activity, besides the increase of neurotransmitter levels, are also being explored as leads for chemotherapeutic treatment of AD. These include the prevention of glutamate-mediated neurotoxicity by antagonism ofN-methyl-D-aspartate (NMDA) receptors, antioxidants, antiinflammatories and inhibitors of fl-amyloid synthesis, but these are not covered to any extent in this chapter. 

To the best of our knowledge, no studies with child and adolescent depressed cohorts have examined hippocampal volume. The one study that examined hippocampal volume in children and adolescents with PTSD (n = 43), about half of whom met criteria for comorbid MDD, failed to find evidence of hippocampal atrophy (De Beilis et ah, 1999). This finding is not surprising, as most of the children and adolescents in the study had not experienced more than one episode of depression, and hippocampal atrophy was found to be correlated with total lifetime duration of illness in the prior adult studies cited (Sheline et ah, 1996 Brem-ner et ah, 2000). Developmental factors may also account for the discrepant findings in child and adult studies. For example, age-dependent changes in sensitivity to some forms of N-methyl-D-aspartate (NMDA) receptor blockade neurotoxicity in corticolimbic regions have been reported in preclinical studies, with cell death minimal or absent prepuberty and reaching peak in early adulthood (Father et ah, 1995). 

Farber, N.B., Wozniak, D.E, Price, M.T., Labruyere, J., Huss, J., St. Peter, H., and Olney, J.W. (1995) Age-specific neurotoxicity in the rat associated with NMDA receptor blockade potential relevance to schizophrenia Biol Psychiatry 38 788-796. 

The PA4 peptide and an excessive amount of APP have proved to be neurotoxic. The accumulation of the pA4 peptide between synapses may be responsible for neuronal dysfunction and death (Schubert et al. 1991). PA4 could also modify the N-methyl-D-aspartate (NMDA) receptor, making possible the presence of neurotoxicity via the excitotoxin and calcium pathways [Mattson et al. 1992). Drugs that interfere with these pathways or alter calcium homeostasis have a potential therapeutic role. 

The precise mechanism by which NO causes glutamase neurotoxicity is unknown. Calcium must be required because of the requirement for NMDA- and glutamate-induced NO formation in brain tissue (Garthwaite etal., 1988). Although both NMDA-receptor agonists and sodium nitroprusside induce specific neurotoxicity as well as cyclic GMP formation in brain tissue (Dawson et al., 1991), it is unlikely that cyclic GMP is the ultimate cause of the neurotoxicity. Instead, NO is most likely involved in producing target cell death. One possible mechanistic pathway is that locally synthesized NO and superoxide anion react with each other to yield peroxynitrite anion (Beckman et al., 1990), which can destroy cell membranes either directly via interaction with cellular thiols (Radi et al., 1991) or indirectly via decomposition to hydroxyl and other free radicals (Beckman et al., 1990). 

Unlike many other abused drugs, amphetamines are neurotoxic. The exact mechanism is not known, but neurotoxicity depends on the NMDA receptor and affects mainly serotonin and dopamine neurons. 

Akaike et al. have examined the neuroprotective properties of serofendic acid, a substance isolated from serum. The compound was found to protect neuronal cells from both glutamate and NO. This was attributed to the scavenging of OH radicals (from the decomposition of ONOO-) rather than NO itself.320 Indeed, Ueda and colleagues have demonstrated the formation of both NO and OH in neuronal cells upon stimulation of the NMDA receptor.321 These workers also trapped lipid radicals in the brains of rats undergoing seizures induced by the stimulation of a subset of glutamate receptors with kainic acid. Polyphenols have been shown to exacerbate the neurotoxicity of NO.322... 

Xu Y. and Tao Y. X. (2004). Involvement of the NMDA receptor/nitric oxide signal pathway in platelet-activating factor-induced neurotoxicity. NeuroReport 15 263-266. 

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