Excitotoxicity induced neuronal damage

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). 

Sodium inflow and acute excitotoxicity. Neurotoxicity of excitatory amino acids is a direct consequence of the excessive excitatory depolarization—may be related to a loss of the ionic homeostasis and/or to a depletion of the energetic stocks of the cell (Olney et al. 1986). Neuronal damage could depend on the extracellular presence of sodium accompanied by a passive flow of chlorine and water (Hablitz and Langmoen 1982). Some considerations suggest that the acute excitatory swelling does not explain completely the damages induced by excitatory amino acids (Pulsinelli et al. 1982). 

The proinflammatory effects of HMGBl were studied in the postischemic brain of rats. Ischemia injury in the brain proceeds with excitotoxicity-induced acute neuronal cell death in the ischemic core, followed by delayed damage to the penumbra (Lee et al., 2000b). It was observed that HMGBl was immediately released into... 

A basic molecular step on the pathway of neuronal damage is dysfunction of the mitochondrial complex I. MPTP, rotenone and paraquat are toxins inhibiting complex I. Inhibition leads to the formation of free radicals and, as a consequence, oxidative stress, which makes the cells vulnerable to glutamate excitotoxicity. Complex I dysfunction may also mediate ceU death via caspase-dependent and caspase-indepen-dent apoptosis, necrosis, and inflammation-induced injury [15, 16]. 

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). 

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