About 600,000 Americans suffer ischemic stroke each year, 8% of whom die within 30 days. A further 15-30% are permanently disabled and 20% require institutional care. Direct and indirect costs of stroke are therefore immense. The treatment of ischemic stroke remains one of the most challenging areas of medicine today. At present, only one agent is approved (Alteplase, rt-PA), and for only a brief window of time (onset of symptoms less than three hours). Since many patients present far beyond this three hour window, most patients not surprisingly receive only palliative care. In order to open the window of therapeutic opportunity the pharmaceutical industry is currently focusing on the development of molecules able to protect neural tissue from ischemic damage, particularly agents able to limit apoptosis. Considerable evidence is available supporting a role of apoptosis in cerebral ischemia. While damaged neurons often die from necrosis, apoptosis contributes significantly to cell death subsequent to cerebral ischemia, with apoptosis being predominant when the excitotoxic insult is relatively mild. Mediators of apoptosis are activated following cerebral ischemia, while inhibition of caspases also reduces infarct size in transient focal ischemia. A number of strategies are currently being developed in order to limit neuronal apoptosis. LeadDiscovery has recently focused on glycogen synthase kinase-3 as one such target. Another target is death-associated protein kinase (DAP-kinase), a recently discovered positive mediator of apoptosis. DAP-kinase is a multidomain, calmodulin (CaM)-regulated serine/threonine protein kinase that has been implicated in apoptosis and tumor suppression. Collaborative research emerging from Northwestern and Vanderbilt Universities has, over recent years, rapidly advanced DAP-kinase as a molecular target for stroke treatments. Amongst their advances this group has described the 3-D structure of DAP-kinase's domain and developed an enzyme assay that can serve to identify endogenous substrates as well as inhibitors of this kinase. DAP-kinase has been shown to modulate neural cell death triggered by a variety of pro-apoptotic stimuli such as ceramide and ischemia and moreover, inhibition of DAP-kinase protein expression can limit apoptosis. These data suggest that DAP-kinase inhibitors may be of use during the first few hours to days following cerebral ischemia. Most recently however, the Northwestern/Vanderbilt group has shown that DAP-kinase may have a previously unappreciated role in neuronal development or recovery from injury

December, 2002

Adapted from Velentza et al, Pharmacol Ther 2002 Feb-Mar;93(2-3):217-24

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk