In the “Focus on Cell Death” section of this edition of TherapeuticAdvances we describe how histone deacetylation offers in built protection against ischemic neural cell death. Despite these and other protective mechanisms such about 600,000 Americans suffer ischemic stroke each year, 8% of whom die within 30 days. Current strategies for improving stroke treatments include the identification of molecules that prevent the effects of ischemia (see for example our recent GSK-3 dossier). Within minutes of onset of ischemia, there is a marked increase in glutamate concentration in the affected portion of the brain and this leads to excitotoxicity. Targeting excitotoxic neurotransmitters has represented one approach to limiting the effects of ischemia however to date clinical trials of molecules such as glutamate receptor antagonists have been disappointing. Researchers at CereMedix have recently focussed their attention on the use of growth factors to limit excitotoxic neural cell death and results thus far are promising.

In particular, this group has been exploiting the findings that NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) are neuroprotective in the middle cerebral artery occlusion (MCAO) rat stroke model. Their mechanism of action involves the activation of transcription factor AP-1 that turns on neuronal growth genes. Thus the CereMedix group has been developing short peptides that mimic some of the properties of full-length neurotrophic factors. One such molecule, a 14-amino acid peptide (CMX-9236) with an N-terminal docosahexaenoic acid designed to enhance entry through the blood-brain barrier has been evaluated in primary rat brain cortical cultures. CMX-9236 was found to counteract the excitotoxic effects of glutamate or kainate, reversing the intracellular accumulation of Ca(2+) to normal levels. Administration (i.v.) of CMX-9236 post initiation of ischemia reduced the lesion volumes in the temporary rat MCAO model and the permanent model for stroke. Neurological behavior scores were similarly improved. Dose-response studies indicated a 60-fold activation of AP-1 transcription factor in cells treated with 100 ng/ml of the peptide. These studies illustrate that a small peptide can function as a neuroprotective agent even when administered systemically and further studies into the therapeutic potential of this molecule are eagerly awaited.

Entry date March, 2003

Adapted from Shashoua et al, Brain Res 2003 Feb 14;963(1-2):214-23 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

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