Ischemia animal model

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

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... 

Since the early 1980s, much effort has focused on animal models of acute and chronic neurodegeneration in search of therapeutics for stroke. Neuronal cell death follows strokes, acute ischemic insults, and chronic neurodegeneration, such as Parkinson s disease, Alzheimer s disease (AD), epilepsy, and Huntington s disease. Up to 80% of all strokes result from focal infarcts and ischemia in the middle cerebral artery (MCA), so the commonly used animal models for neuroprotection are produced by temporary or permanent occlusion of the MCA.5 Lesions of the MCA include occlusion by electrocoagulation, intraluminal monofilaments, photochemical effects, thrombosis, and endothelin-1, but all of these models necessitate studying reperfusion events and validating MCA occlusion by behavioral assessments. 

Soriano MA, Tessier M, Certa U, Gill R. 2000. Parallel gene expression monitoring using oligonucleotide probe arrays of multiple transcripts with an animal model of focal ischemia. J Gereb Blood Flow Metab 20 1045. 

Recently, monoclonal antibodies were attached to gas-filled microbubbles using this spacer coupHng technology. Testing in vitro, in a cell culture system, demonstrated selective accumulation of decafluorobutane-based lipid shell MP1950 microbubbles with covalently attached anti-lCAM-1 antibodies, onto the surface of activated endotheUum [8]. Anti-P-selectin antibodies attached to such microbubbles via an avidin-biotin scheme showed selective accumulation in the areas of inflammation and ischemia/reperfusion injury in an animal model [93]. In the latter example, biotin was also connected to the microbubble surface via a flexible polymer spacer arm. 

The transdifferentiation of HSCs into a mature hematopoietic fate (e.g., endothelium) in the heart is less controversial [148]. In animal models of stem cell therapy in ischemic heart disease, the evidence points toward increased neovascularization (with reduced myocardial ischemia) and consequent improvement in cardiac function [149-151]. Bone marrow stem cells may directly contribute to an increase in contractility or, more likely, may passively limit infarct expansion and remodeling. Unfortunately, the limitations of the present animal models leave this question unanswered. 

In animal models, milk thistle purportedly limits hepatic injury associated with a variety of toxins, including Amanita mushrooms, galactosamine, carbon tetrachloride, acetaminophen, radiation, cold ischemia, and ethanol. In vitro studies and some in vivo studies demonstrate that silymarin reduces lipid peroxidation, scavenges free radicals, and enhances glutathione and superoxide dismutase levels. This may contribute to membrane stabilization and reduce toxin entry. 

Jacobson KA, Hoffmann C, Cattabeni F, Abbracchio MP (1999) Adenosine-induced cell death evidence for receptor-mediated signalling. Apoptosis 4(3) 197—211 Kafka SH, Corbett R (1996) Selective adenosine A2A receptor/dopamine D2 receptor interactions in animal models of schizophrenia. Eur J Pharmacol 295(2-3) 147-154 Latini S, Bordoni F, Corradetti R, Pepeu G, Pedata F (1998) Temporal correlation between adenosine outflow and synaptic potential inhibition in rat hippocampal slices during ischemia-like conditions. Brain Res., 794, (2) 325-328. 

Table 10.1 Use of NMDA receptor antagonists for the treatment of ischemia in animal models...

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... 

Ischemia results from an imbalance of oxygen supply and demand. In patients with ACS, multiple studies of atheroma have implicated inflammation as a critical part of the syndrome. Signs of inflammation in animal models and humans occur with lipid accumulation in the artery wall and plaque development. Plaque rupture and thrombosis have abruptly narrowed or occluded the coronary arteries precipitating ACS (14). 

---