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 is 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, not surprisingly most patients 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 (see for example our recent report implicating glycogen synthase kinase-3 inhibitors in the treatment of stroke). Considerably 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.

The development of strategies able to limit apoptosis in the face of cerebral ischemia is therefore becoming increasingly attractive. In another recent dossier (click here for access) we analyze the therapeutic potential of the “Inhibitor of Apoptosis Protein” (IAP) family and conclude that IAPs such as NAIP1 and XIAP may represent excellent targets for novel stroke therapies. While inhibitors of apoptosis are becoming increasingly attractive for the treatment of cardiovascular disorders, those that stimulate apoptosis are being developed for the treatment of cancer. In yet another recent dossier we describe the therapeutic potential of histone deacetylase (HDAC) inhibitors (click here for access). Although this therapeutic class is highly attractive, data recently published by researchers at the University of Strasbourg urges caution since histone deacetylation appears to play a key role in neuronal survival. In particular the treatment of primary neurons with standard HDAC inhibitors, trichostatin A or sodium butyrate induces typical features of apoptosis. This was shown to be partly dependent on the activation of the transcription factor E2F-1, which has pro-apoptotic functions in these neurons, and E2F-dependent genes, such as its cell cycle target cyclin E, and also pro-apoptotic genes, such as Apaf1. Histone deacetylase activity therefore appears to allow a constitutive repression of E2F-dependent gene transcription in mature neurons in order to ensure survival and blockade of this function by the use of HDAC inhibitors could thus be fatal for neurons.

These data raise the possibility that HDAC inhibitors could jeopardize neuronal viability. Molecules developed for the treatment of cancer should therefore have limited blood brain barrier permeability or alternatively they should specifically target cancer cells. This concept of selectivity represents a major theme of our HDAC dossier in which we discuss strategies that could be employed to specifically target those genes involved in tumor progression. In addition it should be noted that the effects of HDAC inhibitors on neural survival discussed in the present paper were concentration dependent and the possibility that cancer cells and neurons differ in their sensitivity to HDAC inhibitors should be evaluated.

Entry date March, 2003

Adapted from Boutillier et al, J Neurochem 2003 Feb;84(4):814-28 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

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