Stroke is the third leading cause of death in the industrialized world, and affects annually over 2 million people worldwide. About 25% of patients die within the first year following stroke and an additional 30-40% remain permanently disabled. Protection of the brain from acute ischemic stroke has been difficult to achieve clinically and failed approaches include glutamate receptor blockers, ion channel blockers, free radical scavengers and leukocyte inhibitors.

Starting anew, AGY’s scientists approached this challenge in a fundamentally different way. AGY wanted to understand the molecular pathological signaling pathways triggered by the lack of oxygen and glucose supply to the cortex, as well as those involved in post-ischemic regeneration. Its scientists and their collaborators pioneered a comprehensive approach to the molecular understanding of pathological, protective, and regenerative processes that follow a stroke.

The company utilized models of ischemic damage, including the middle cerebral artery occlusion model (MCAO), ischemic preconditioning/tolerance, as well as the “enriched environment” model, in order to sample tissues at different times and to derive pathways of post-ischemic damage, and plasticity. The company employed its proprietary imAGYne™ cloning and bioinformatics platform to identify and validate novel protein targets.

Processing temporal and spatial expression information at high resolution from thousands of tissue samples resulted in a broad and fundamentally new understanding of signaling pathways controlling cellular events after ischemia. These pathological pathways involve neuronal, glial and endothelial interactions. Drug targets within these pathways have been selected and characterized and drug screens to identify inhibitors have been performed. Consequently, compounds modulating these targets have been proven to be neuroprotective or active in neuroregeneration.

An additional approach to unravel pathological mechanisms in stroke included the screening for neuroprotective activities of compounds with known targets and pharmacology. This approach led to the identification of novel pathological pathways that control ischemic cell death as well as to highly neuroprotective compounds modulating these pathways.

AGY’s unique approach of integrating information from functional and chemical genomics led to a fundamental understanding of processes controlling neuronal death and functional regeneration after stroke and a series of compounds displaying neuroprotective or neuroregenerative activities in vivo.
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