Excitotoxic cascade/excitotoxicity

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). 

The last phase of the excitotoxic cascade involves the activation of various biochemical pathways, among which phospholipases, proteases (in particular cal-pain), kinases and calmodulin-regulated enzymes such as nitric oxide synthase (NOS) play a prominent role. 

All these genetic factors may interact in still-unknown genetic networks, leading to a cascade of pathogenic events characterized by abnormal protein processing and misfolding with snbseqnent accnmnlation of abnormal proteins (conformational changes), nbiqnitin-proteasome system dysfunction, excitotoxic reactions, oxidative... 

FIGURE 10-28. Cellular events occurring during excitotoxicity (part 2). The internal milieu of a neuron is very sensitive to calcium, as a small increase in calcium concentration will alter all sorts of enzyme activity, as well as neuronal membrane excitability. If calcium levels rise too much, they will begin to activate enzymes that can be dangerous for the cell owing to their ability to trigger a destructive chemical cascade. 

To review the neuropathology of Alzheimer s disease, and its relationship to the amyloid cascade hypothesis and the glutamate excitotoxic hypothesis of Alzheimer s disease. 

Ca2+ influx mediates excitotoxicity with a cascade of events involving free radical generation, mitochondrial dysfunction, and the activation of many enzymes (Table 7.1), including those involved in the generation and metabolism of arachi-donic acid (Farooqui and Horrocks, 1991,1994b Farooqui et al., 2001 Wang et al.,... 

In primary cultures of neonatal cerebellar granule neurons, all Ca2+ sensors, calmodulin, protein kinases C (PKC), and the p21(ras)/phosphatidylinositol 3 -kinase (Ptdlns-3K)/Akt pathway, converge towards NF-kB at the levels of nuclear translocation as well as transcription. The duration of NF-kB activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on the different upstream and downstream signaling associated with various kinases. This is in contrast to studies in non-neuronal cells, which either do not respond to Ca2+ or do not simultaneously activate all three cascades (Lilienbaum and Israel, 2003). Collective evidence suggests that brain inflammatory processes differ from systemic inflammation not only in the involvement of various types of neural cells but also in differences in response to second messengers. 

The partial or complete interruption of the blood flow to the retina, as well as in other tissues, leads to neuronal death through a complex series of biochemical events triggered by the excitotoxic cascade. 

The extent of spinal cord injury depends on the severity of the initial trauma as well as the level of subsequent injury. The primary impact of contusion injury triggers a cascade of secondary events including hemorrhage, ischemia, excitotoxicity... 

In order to refine therapeutic regimes and thus prevent chemical warfare agent-induced excitatory neurodegeneration in exposed individuals (Figure 5.4), a more comprehensive characterization of the destructive signal-transduction mechanisms and intracellular enzymatic cascades associated with glutamate receptor mediated delayed excitotoxicity (PCD) is needed. Accordingly, the refinement of therapeutic... 

It is commonly believed that Ca is a major mediator of neuronal cell death in ischemia, especially in areas where the release of glutamate causes secondary excitotoxic damage. There are also data that show that a slight rise in intracellular Ca can protect a neuron from adverse events of ischemia (Wang et al., 2002). Since ischemia triggers a plethora of other adverse events, some of which do not directly involve Ca, the specific role of intracellular Ca in triggering neurotoxic cascades has mostly been studied in cell culture models. Direct extrapolation of these results for in vivo conditions is problematic. 

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