NMDA channel

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. 

Effects of NMDA channel blockade and increased limbic system metabolism on subsequent sleep... 

Campbell, I. G. Feinberg, I. (1996a). Noncompetitive NMDA channel blockade during waking intensely stimulates NREM delta. J. Pharmacol Exp. Then 276, 737-42. 

The hippocampus has innumerable afferent and efferent connections to other brain structures both within the limbic system and beyond. There are receptors for many different chemical signals ranging from the "classical neurotransmitters such as acetylcholine to steroid hormones and neurotrophic factors. Some of these receptors are located in the synapses that form the intrinsic hippocampal circuits and others are the targets of specific projection pathways from other brain areas. A comprehensive review of all neurotransmitter interactions relevant to function is not within the scope of this chapter. There are detailed reviews of modulation of neurochemical systems on place learning in the watermaze (McNamara and Skelton, 1993) or other limbic-system dependent tasks (Izquierdo and Medina, 1995) in animals. The effects of key neurochemical, other than NMDA channel-mediated, and environmental influences are discussed below. 

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). 

GABA-A or NMDA channels, within the central nervous system (i.e., the brain). The term anesthesia may therefore be defined as a reversible suppression of sensation (particularly to pain) with or without loss of consciousness, depending whether it is local or general anesthesia. 

Dextromethorphan and its O-demethylated metabolite dextrorphan (morphinans), are also low to medium affinity NMDA channel blockers. The former has been in clinical use as an antitussive for about 40 years and could therefore be considered as a very safe drug (Bern et al., 1992). 

Houghton, A. K., Parsons, C. G., Headley, P. M. Mrz2/576, a fast kinetic NMDA channel blocker, reduces the development of morphine tolerance in awake rats, Pain 2001, 91, 201-207. 

Specific inhibitors of NMDA channels include a 27-residue "spasmotic" conotoxin,490 2-amino-4-phosphonobutyrate, related longer chain aminophos-phonates, and the following potent anticonvulsant drug, which is able to penetrate the blood-brain barrier.677... 

NMDA channels K + transport Katp channels Apigenin Epigallocatechin gallate... 

Yu XM, Askalan R, Keil GJ 2nd, Salter MW (1997) NMDA channel regulation by channel-associated protein tyrosine kinase SRc. Science 275 74-8... 

Glutamate receptor antagonists - NMDA channel blocker cerestat,... 

Moreover, if AMPA density falls below a critical threshold, levels of depolarization are insufficient to unblock NMDA channels, preventing postsynaptic depolarization or Ca2+ influx. The lack of Ca2+ influx prevents subsequent AMPA receptor insertion into the postsynaptic membrane. Thus, such synapses, despite containing intact NMDA receptors, are functionally silent and cannot be recovered by electrical stimulation alone (Isaac et al., 1999). This silencing of synapses could limit the degree of recovery to be expected even if normal glutamatergic functioning could be restored. 

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