Excitotoxicity receptors

Lynch DR, Guttmann RP (2002) Excitotoxicity perspectives based on N-methyl-D-aspartate receptor subtypes. J Pharmacol Exp Ther 300(3) 717-723 Magnuson DS, Knudsen BE, Geiger JD, Brownstone RM, Nath A (1995) Human immunodeficiency virus type 1 tat activates non-N-methyl-D-aspartate excitatory amino acid receptors and causes neurotoxicity. Ann Neurol 37(3) 373-380 Mamdouh Z, Chen X, Kerini LM, Maxfield FR, Muller WA (2003) Targeted recycling of PECAM from endothelial surface-connected compartments during diapedesis. Nature 421(6924) 748-753... 

The purported prophylactic use of Japanese herbal medicines to combat neuronal ageing has been related to their free-radical scavenging activity (Hiramatsu a al., 1992). Inhibition of the pro-inflammatory effects of cytokine interleukin-1 by recombinant endogenous interleukin-1 receptor antagonist in experimental rats is associated with alleviation of excitotoxic neuronal damage, an action which has also been related to the antiinflammatory effect of lipocortin 1 (Relton and Roth well, 1992). 

Relton, J.K. and Rothwell, N.J. (1992). Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damr e in the rat. Brain Res. Bull. 29, 243-246. 

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). 

N-Nitro-L-arginine methyl ester (L-NAME) is an inhibitor of NOS L-NAME reportedly reduces the volume of cortical and striatal infarct after middle cerebral artery occlusion in the rat. This protection can be reversed by co-injection of L-arginine. L-NAME also reduced the excitotoxic damage induced by NMDA injection. Finally, the authors showed that L-NAME reduced glutamate efflux produced by ischaemic injury in rats. The authors concluded that NOS induced by NMDA receptor overstimulation is a key event in the neuronal injury cascade (Buisson eta/., 1993). 

Excitotoxicity Direct and Indirect Activation of Glutamate Receptors... 

Nonaka S, Chuang DM. Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N -methyl-D-aspartate receptor-mediated calcium influx. Proc Natl Acad Sci USA 1998 95 2642-2647. 

Intracerebroventricular injection of kainic acid has been shown to result in a well-characterized pattern of neuronal cell damage. In the hippocampus, kainic acid causes a selective lesion of the CA3 pyramidal neurons, an area rich in KA1 and GluR6 receptors. The lesion does not compromise passing axons, which is why this type of (excitotoxic) lesion is often referred to as axon-sparing . Kainic acid injection into the hippocampus also leads to epileptiform discharges in cells normally innervated by the damaged pyramidal neurons. 

V-methyl-D-aspartate receptors. Glutamate is the major excitatory neurotransmitter in the central nervous system (Ch. 15). Its receptors can be divided into three types AMPA/kainate, NMDA and metabotropic receptors. NMDA receptors are composed of two different types of subunit - NR1 and NR2. They play an important role in the induction of synaptic plasticity and excitotoxicity. 

Both NMDA and AMPA/kainate receptors contribute to excitotoxic neuronal degeneration of neurons and glia 563 Excitotoxicity leads to increased Ca2+ and Zn2+, which can activate cytotoxic intracellular pathways 564... 

Both NMDA and AMPA/kainate receptors contribute to excitotoxic neuronal degeneration of neurons and glia. 

In vitro studies on excitotoxicity suggest that while both NMDA and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate (KA) receptors can mediate excitotoxicity (see Ch. 15), these classes of glutamate receptors do not do so equally. Experiments with cortical or hippocampal cell cultures suggest that much of the neuronal death associated with brief, intense glutamate exposure is mediated by NMDA receptor activation, probably because this can induce lethal amounts of Ca2+ influx more rapidly than can AMPA/KA receptor stimulation. 

However, overactivation of AMPA or KA receptors can also lead to intracellular Ca2+ overload and neurodegeneration. This maybe especially true under conditions where NMDA-receptor activity is reduced by extracellular acidity or a buildup of extracellular Zn2+ [ 12]. It is also true with respect to specific neuronal subpopulations that express AMPA-sensitive Ca2+ channels (see Ch. 15). G-protein-linked metabotropic glutamate receptors (mGluRs) appear not to mediate excitotoxicity directly but, rather, to modify the degree of excitotoxic injury. 

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