Ischaemic tissue

McCord, J.H. (1985). Oxygen-derived free radicals in post-ischaemic tissue injur). N. Engl. J. Med. 312, 159-163. 

The mechanism for the production of O2" in ischaemic tissue appears to involve changes in purine metabolism within ischaemic cells. Sublethal hypoxia decelerates mitochondrial oxidative phosphorylation, rendering the production of ATP dependent upon the... 

Although numerous structural types have been synthesized to date, we expect research to continue in this area. Several companies, not mentioned here, have ongoing Class III discovery programmes. As medicinal chemists begin to take advantage of information from new pharmacological studies and clinical experience, we expect to see agents with increased selectivity (for example, normal vs. ischaemic tissue), improved efficacy and improved safety. 

Clearly, in the normal individual, iron levels are under extremely tight control and there is little opportunity for iron-catalysed free radical generating reactions to occur. However, there are situations when the iron status can change, either locally, as in ischaemic tissue, or systematically, as with idiopathic haemochromatosis or transfusion-induced iron overload. In such circumstances, abnormal levels of iron can induce toxic symptoms. 

Localised and temporary elevation of iron levels 7.1. Ischaemic tissue... 

There is increasing evidence for the beneficial influence of the presence of iron chelators during reperfusion of ischaemic tissue. Clearly Reactions (i), (iii) and (iv) of Scheme 1 do not occur in the absence of loosely bound iron and it is such species which are efficiently scavenged by desferrioxamine (Structure 1, Scheme IB) forming the chemically inert iron complex, ferrioxamine. Thus the... 

Cardiac arrhythmias result from reperfusion of ischaemic tissue. These vary in type and are often transient, a factor which may influence the decision whether or not to treat. 

In experimentally induced brain focal ischaemia, the upregulation of ICAM-1 and the induction of E- and P-selectm1719 is believed to result from the activity of inflammatory cytokines such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6), which are produced by the ischaemic brain20-21 or by the reoxygenation of microvascular endothelial cells.22 There is a direct association between increased expression of ICAM-1 andE-selectin,19-23 the appearance of inflammatory cytokines,20 and the degree of polymorphonuclear (PMN) cell infiltration into ischaemic tissue. Moreover, cultured murine brain microvascular endothelial cells stimulated with IL-1 () or TNF-a express E-selectin and ICAM-1 and support neutrophil adhesion.24... 

Once recmited into ischaemic tissue, neutrophil-mediated injury could arise from the release of free radicals and/or cytotoxic enzymes.5 Activation of neutrophils... 

In conclusion, this section has highlighted the potential pathogenic contribution of blood neutrophils to the CNS injury that accompanies the ischaemia-reperfusion injury of stroke. From experimental models of this disorder, it appears that the second wave of tissue damage is induced either by neutrophil-mediated vasoocclusion or by the infiltration of neutrophils into the ischaemic tissue with concomitant release of lytic factors. Antagonising both neutrophil attachment to endothelium and the transendothelial migration of these cells at the level of the blood-brain barrier is likely to be of clinical benefit to cerebral ischaemia-reperfusion injury. Consequently, it is anticipated that a further unravelling of the mechanisms that promote neutrophil interaction with cerebral vessel walls will lead to the introduction of a more specific therapeutic intervention for the treatment of stroke. 

Reperfusion to restore the flow of oxygenated blood to ischaemic tissue is essential for its survival but it produces oxygen free radicals, which are thought to be responsible for reperfusion-induced injury. 

Xanthine oxidase can reduce nitrate to nitrite (Westerfield et al. 1959, Fridovich and Handler 1962). Xanthine oxidase and dissimilatory nitrate reductase share structural similarities. Both are molybdoenzymes and contain flavin adenine dinucleotide and Fe/S clusters (McCord 1985, Mitchell 1986, Payne et al. 1997). Zhang et al. (1998) reported that both purified bovine buttermilk xanthine oxidase and xanthine oxidase-containing inflamed human synovial tissue can generate NO by reducing nitrite in the presence of NADH. This nitrite reductase activity of xanthine oxidase may act as a supplement to the activity of nitric oxide synthase (NOS) to redistribute blood flow to ischaemic tissues when NOS activity is absent. 

Nonsedimentable cathepsin D (EC 3.4.23.5) activity was significantly elevated in ischaemic tissue by... 

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