Models of ischemia

Ischemia-reperfusion is thought to mediate the severe organ dysfunction witnessed after shock or cardiac arrest. HSPs could play a major role in the defence against ischemia-reperfusion injury. Many in vivo experimental models of ischemia and/or ischemia-reperfusion have demonstrated HSP induction. 

Thrombolytics and drugs targeting several injury pathways have shown efficacy in models of hypoxia-ischemia. A number of neuroprotective strategies have been identified in animal models of ischemia, and many... 

NO is a neuronal messenger molecule whose overproduction can initiate neurotoxic events under pathological conditions. NO production has clearly been linked to neurodegeneration in animal models of ischemia and in vitro cultured cells. The final cellular pathways that lead from... 

Although several potential therapeutic agents have been tested in animal models of ischemia/reperfusion heart injury with some success, nearly none of the specific antiapoptotic agents have reached the stage of clinical research [172]. The studies which have examined the effect of caspase inhibitors on ischemia/reperfusion models are summarized in Table 2. Broad-spectrum caspase inhibitors have been shown in many studies to reduce cardiomyo-cyte apoptosis, to reduce the size of MI, and to preserve heart function after MI [173-175, 178, 181]. The protective effect of caspase inhibitors can be seen when these agents are administered before or after the onset of ischemia but are most prominent when introduced before the onset of reperfusion [172, 175, 178]. Selective caspase inhibitors, on the other hand, have been reported to have varying effect they have been found to reduce cardiomyocytes apoptosis, but the infarct size remained unchanged [177, 178, 181],... 

Studies Showing the Effect of Treatment with Caspase Inhibitors in Experimental Models of Ischemia/Reperfusion Injury to the Heart0... 

Young W., RappaportZ. H., Chalif D. J., and Flamm E. S. (1987) Regional brain sodium, potassium, and water changes in the rat middle cerebral artery occlusion model of ischemia. Stroke 18, 751-759. 

Delay neuroprotective treatment-hypothermia by a minimum time interval (preferably 30 min or more) after ischemia onset Sustained neuroprotection at prolonged (weeks/months) time point Efficacy in multiple models of ischemia, particularly permanent ischemia models... 

PBN failed to exert a cardioprotective role in our model of ischemia and reperfusion. There are a number of possibilities that may explain the absence of any protective effect. Firstly, PBN may not have gained access to the site where the hydroxyl radical is generated. Failure to deliver PBN to this locus of radical production would exclude any possible protective effect for this spin trap. Secondly, the kinetic reaction between a radical species and the spin trap is rather inefficient. Thus PBN may trap only a small fraction of the total amount of hydroxyl radical produced. Thirdly, in the aqueous environment of the myocardial cell the PBN/ OH adduct formed is unstable and spontaneously decomposes into benzaldehyde and the tert-butylhydroaminoxyl radical. These toxic breakdown products are more stable than the parent molecule and may diffuse from their site of production to other areas, resulting in an extension of tissue injury. Fourthly, we must acknowledge the possibility that the hydroxyl radical contributes only minimally to myocardial cell injury in this model. 

Christensen, C.W. Reeves, W.C. Lassar, T.A. Schmidt, D.H. Inadequate subendocardial oxygen delivery during perfluorocarbon perfusion in a canine model of ischemia. Am. Heart J. 1988,115, 30-37. 

Renal ischemia/reperfusion injury in vivo activates caspase-1 and caspase-3 [62, 70]. In a murine model of ischemia/ reperfusion injury, ZVAD-fmk, a pancaspase inhibitor, was shown to attenuate reperfusion-induced DNA damage (as determined by TUNEL assay) and inflammation [65]. Down-regulation of caspase-3 and caspase-8 by siRNA provided protection from acute kidney injury in a mice model of ischemia-reperfusion injury (71). Recent studies by Edelstein et al. [66, 72] help estabhsh a hnk between the inflammatory aspects of the ischemic/reperfusion injury and caspase activation. In these studies it was observed that caspase 1 deficient mice were protected from ischemia-reperfusion... 

Two major forms of cell death are recognized in the pathology of myocardial injury the necrotic cell death and the apoptotic cell death. The exact contributions of the necrotic and apoptotic cell death in myocardial cell injury is unclear. Both forms of cell death occur in experimental settings of ischemia and reperfusion. Necrotic cell death was shown to peak after 24h of reperfusion and apoptotic cell death was increased up to 72 h of reperfusion, in a canine model of ischemia and reperfusion.1 Furthermore, apoptotic cell death can evolve into necrotic cell death and pharmacological inhibition of the apoptotic signaling cascade during the reperfusion phase is able to attenuate both the apoptotic and necrotic components of cell death.2,3 Apoptosis and necrosis seem to share common... 

Endothelin-1 is a potent vasoconstrictor peptide derived from endothelial cells.100 Its physiological function is mediated by two receptors the ET-A and ET-B. Table 1. Figure 11. ET-A and ET-B receptors are located in vascular smooth muscle and their activation causes vasoconstriction, whereas ET-B receptor is also located in the endothelium and its activation results in vasodilation by increasing nitric oxide or prostacyclin. Endothelin is released following myocardial ischemia and reperfusion. Endothelin reduces infarct size in a perfused rat heart model of ischemia and reperfusion through activation of protein kinase C and KATp channel.101 Furthermore, in neonatal rat ventricular myocytes, endothelin is shown to activate the calcineurin-NFAT (nuclear factor of activated cells) pathways and enhance the expression of Bcl-2.102 However, endogenous blockade of endothelin at the level of the ET-A receptor reduced infarct size in a pig model of coronary occlusion and reperfusion.103... 

Prostacyclin is increased in response to ischemia and reperfusion through activation of the cyclooxygenase-2 pathway. Inhibition of cyclooxygenase-2 by celecoxib or meloxicam resulted in a concentration dependent exacerbation of the myocardial dysfunction and damage in a perfused rabbit heart model of ischemia and reperfusion, indicating a cardioprotective role for prostacyclin.104... 

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