(National Research Council Canada, Institute for Biological Sciences, Ottawa, ON)
Title of Presentation: "A framework for pursuing neuroprotection in cerebral
ischemia developed from a "Stroke in a dish" model"
[Host: Dr. John Mielke]
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Abstract: Neuroprotection clinical stroke trials have failed. Major issues remain to be resolved at the preclinical level: (i) timing (time is brain), efficacy and adverse effect issues have not been adequately addressed; (ii) lack of prioritization of targets in the neurotoxic signaling cascade induced by ischemia and; (iii) drug discovery programs fail to prioritize among an ever burgeoning number of neuroprotective candidates. Using a stroke-like model in neuron cultures, oxygen-glucose deprivation (OGD), a neuroprotective framework has been developed. First, screening of agents which pre-emptively precondition neurons reveals convergence at a common neurotoxic target, which is to suppress cellular glutamate release during OGD. However, this glutamate release is not prevented during prolonged OGD, representing a ceiling of neuroprotection. Second, administration of an anti-excitotoxic receptor antagonist drug cocktail immediately prior to glutamate release during prolonged OGD preserves neuroprotection. However, prolonging OGD even further results in a second ceiling of neuroprotection, which necessitates a more aggressive anti-excitotoxic drug cocktail. In summary, pre-emptive preconditioning buys time before requiring acute rescue with a drug cocktail. This framework addresses what is required for neuroprotection, but not what may be clinically possible. To gauge if the neuroprotective framework can be tolerated, investigations of spatiotemporal patterns of network activity and functional connectivity are in progress using neurons cultured on multi-electrode arrays.
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