Excitotoxicity mediated

Table 7.1 Excitotoxicity-mediated alterations in enzymic activities in brain tissues...

Table 7.2 Excitotoxicity-mediated changes in neurochemical parameters involved in oxidative stress...

Findings obtained from experimental studies suggest that induction of iNOS mediates inflammatory or ischemic brain damage and that excessively activated nNOS under excitotoxic or ischemic conditions produces NO that is toxic to surrounding neurons. Selective inhibition of iNOS or nNOS may be neuroprotec-tive. This is also the case in glaucoma and diabetic... 

The proposal that NO or its reactant products mediate toxicity in the brain remains controversial in part because of the use of non-selective agents such as those listed above that block NO formation in neuronal, glial, and vascular compartments. Nevertheless, a major area of research has been into the potential role of NO in neuronal excitotoxicity. Functional deficits following cerebral ischaemia are consistently reduced by blockers of NOS and in mutant mice deficient in NOS activity, infarct volumes were significantly smaller one to three days after cerebral artery occlusion, and the neurological deficits were less than those in normal mice. Changes in blood flow or vascular anatomy did not account for these differences. By contrast, infarct size in the mutant became larger... 

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). 

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. 

Glutamate-mediated excitotoxicity contributes to ischemic neuronal death 288... 

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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