For example, blood pressure lowering agents such as the ACE inhibitors, developed originally to reduce the risk of vascular injury and myocardial infarction were found to reduce stroke incidence ,. atherosclerosis or embolus formation . The sequence of events, termed the ischaemic cascade, that follows an ischaemic stroke has also been established . Here, neurons exposed to extreme reductions in blood flow (the ischaemic core) drop their membrane potential, undergo irreversible structural damage, and die. In surrounding regions (the ischaemic penumbra) the reduction in blood flow is sufficient to compromise neuronal function but not immediately cause neuronal death. A balance between energy supply and consumption exits and tissue survival is determined by the depth and duration of ischaemia ,. An understanding of this process has led to the concept of reperfusion and neuroprotective therapies. Twenty Years of Rapid but Inherited Advances Interestingly, many therapeutic advances in stroke have come from research in other disciplines. For example, blood pressure lowering agents such as the ACE inhibitors, developed originally to reduce the risk of vascular injury and myocardial infarction Darusentan were found to reduce stroke incidence ,. Similarly for the statins, designed to reduce LDL-cholesterol were found to protect against stroke . Thrombolysis and anti-platelet therapies developed from ischaemic heart disease management , and hemicraniectomy to relieve pressure in some cases of ischaemic stroke was used in head trauma . Even some stroke care unit management practices have come from approaches developed in cardiology, oncology, burns, and transplant medicine . We have inherited the majority of four categories of acute and five of secondary prevention interventions with level 1 evidence of benefit in stroke since 1978 in this way (see Table 1). As this approach has been successful in the past, abandoning it now would be unwise: we suggest a continued monitoring of other disciplines, while also pursuing novel stroke-specific research. We will address the likely wins from existing classes of intervention and then speculate from where the next therapeutic classes may emerge. Table 1 Acute interventions and secondary prevention strategies of confirmed benefit based on level I evidence. gene , which is usually involved in cell signalling and fate during embryonic development. Subsequently, a candidate gene approach using case-control designs produced a large number of potential gene polymorphisms, many of which could not be replicated and were probably the product of underpowered studies. The emergence of the concept of polygenic contributions to the stroke syndrome, gene chip technology and genome-wide association Darusentan studies (GWASs) has revolutionized the area. Large international cooperative Rabbit Polyclonal to OR52E2 studies with sample sizes in the thousands have enabled investigators to produce reliable data. For example, by genotyping more than 310,000 single-nucleotide polymorphisms (SNPs) in more than 1,700 intracranial aneurysms and 7,400 controls, SNPs on Chromosomes 2q, 8q, and 9p were associated with aneurysmal presence. The biological implications come from an understanding of the function of these genes as our research effort explores their biology. Chromosomes 8q and 9p both have genes that are associated with progenitor cells and expressed in blood Darusentan vessels. The main candidate gene on 8q is em SOX17 /em , which is required for endothelial formation and maintenance . The implications for the development of gene-based or other therapies are obvious. Similarly, investigators of the International Stroke Genetics Consortium found an association between SNPs in the Chromosome 9p21.3 region and large-artery stroke . GWASs are still in their infancy and Darusentan are dependent on careful phenotyping and large sample sizes. However,.
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