NMDA blocker

Crill I want to make it clear that although I referred to these as Ca spikes, there are probably other inward currents involved. In every cell that we have examined we could block the plateau of response under Ca spikes with cadmium, but in a few cells we could also block it with NMDA blockers or TTX. There seems to be some variation, but primarily the charge carrier seems to be Ca. ... 

In addition to halopeiidol, the putative neuroleptics, limcazole (311), lemoxipiide (312), and gevotioline (313) bind to (7-ieceptois as does the dopamine uptake blocker, GBR 12909 (314) and two ligands active at the NMDA receptor, ifenprodil (315) and CNS 1102 (316). NPC 16377, (317) is a selective (7-teceptor ligand. MAO inhibitors and antidepressants also bind to (7-teceptors. Some evidence indicates that (7-teceptors in the brain are in fact a form of cytochrome which may account for the diversity of ligands interacting with (7-sites. 

Psychotomimetic Drugs. Figure 2 Chemical structures of the dissociative anesthetics phencyclidine (PCP) and ketamine. Both are arylcycloalkylamine derivatives that are open channel blockers of the NMDA channel. 

The NRl family is composed of one subunit with nine different alternatively spliced variants. Block by NMDA channel blockers such as ketamine, MK-801 and phencyclidine is affected by which splice variant of the NRl subunit is involved, probably because the NRl splice variant affects the kinetics of channel activation (the effectiveness of any channel blocker being dependent on how much the channel is open). The glycine binding site is on the NRl subunit and the glutamate binding site is on the NR2 and NR3 subunits. 

The ion-channel blocking mechanism has been widely tested and found to be important in both pharmacology and physiology. Examples are the block of nerve and cardiac sodium channels by local anesthetics, or block of NMDA receptor channels by Mg2+ and the anesthetic ketamine. The channel-block mechanism was first used quantitatively to describe block of the squid axon K+ current by tetraethylammonium (TEA) ions. The effects of channel blockers on synaptic potentials and synaptic currents were investigated, particularly at the neuromuscular junction, and the development of the single-channel recording technique allowed channel blockages to be observed directly for the first time. 

Initial evidence linking Hebb s coincidence detection rule to learning and memory. As the unique receptor in the brain with the coincidence-detection property, the NMDA receptor is an ideal candidate to gate the formation of memory at the synaptic level. Early observations demonstrated that infusion of NMDA receptor blockers into brain ventricles resulted in animals poor performance in the hidden-platform water maze. At first, this seemed to provide evidence for the role of hippocampal LTP in memory formation. Unfortunately, careful analyses revealed that poor performances in the water maze tests... 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia. The hypothesis that hypofunction of a subpopulation of NMDA receptors contributes to the pathophysiology of schizophrenia has gained considerable support over the last decade (see Fig. 54-1). The dissociative anesthetics including phencyclidine (PCP) and ketamine when introduced clinically 40 years ago were noted to produce a syndrome that was difficult to distinguish from schizophrenia. These agents act as noncompetitive open-channel blockers of the NMDA receptor. 

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+... 

Ketamine acts as a blocker (or antagonist ) of the NMDA receptor. PCP also acts as an antagonist of the NMDA receptor, as does alcohol, although much less potently. NMDA receptors are present in numerous brain regions, and ketamine is thought to produce its effects by blocking NMDA receptors in a number of brain regions, as shown in Table 6.1. 

The evidence given above is probably sufficient to consider glutamate antagonists as plausible neuroprotective treatment of ALS. Unfortunately, most clinical trials with glutamate antagonists completed to date have not been encouraging. Dextromethorphan (NMDA channel blocker) showed no benefit (Blin et al. 1996 Gredal et al. 1997). 

Although the hypothesis underlying the ability of this moderate affinity open channel blocker to differentiate between phasic physiological and tonic excitotoxic pathological activation of NMDA receptors has gained relatively wide acceptance (Mealing et al. 1997 Kornhuber and Weller 1997 Parsons et al. 1999) it is still unclear how such compounds could differentiate between normal and abnormal synaptic activation of NMDA receptors. 

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