Northwestern widens ’treatment window’ for brain injury and stroke

In the treatment of stroke, there is currently only a three-hour “window of therapeutic opportunity” to prevent additional brain cell damage and only one medication approved to improve blood flow to oxygen-deprived neurons near the injury, thereby minimizing potentially debilitating side effects.

Now, scientists from Northwestern University report that a single injection of a chemical they created — given up to six hours after brain injury or stroke — protects against additional brain cell death for a week or longer. An article describing the new compound and its activity in the body appears in the September online issue of the Bioorganic and Medicinal Chemistry Letters.

The compound inhibits activity of an enzyme called death-associated protein kinase (DAPK), known to be an early player in the chain of molecular events leading to apoptosis, or programmed cell death. Earlier studies showed that levels of DAPK increase markedly prior to neuron death and that apoptosis increases rapidly hours after the onset of a stroke in laboratory models.

“Results of this study support the idea that targeting protein kinases, which function early in programmed cell death pathways, could identify new therapeutic approaches to acute brain injury,” said Northwestern scientist Martin Watterson, who led the study. Watterson is John G. Searle Professor of Molecular Biology and Biochemistry, professor of molecular pharmacology and biological chemistry at the Feinberg School of Medicine and director of the Drug Discovery Program at Northwestern University.

The timing of DAPK’s increase in those early studies, coupled with its ability to initiate cell death, suggested to Watterson and co-researchers that a drug that inhibits DAPK activity might prevent or reduce neuron death in the critical period following brain injury or stroke.

The researchers created a small-molecule DAPK inhibitor based on data derived from their own earlier experiments. They had developed a quantitative assay for DAPK that subsequently helped them design methods for identifying candidate DAPK inhibitors, and later, with collaborators at Vanderbilt University, determined the three-dimensional structure of a region on the DAPK molecule that is essential to triggering programmed cell death.

While initial results with the DAPK inhibitor provide a precedent for drug discovery research in acute brain injury, Watterson explained that the compound’s molecular properties did not make it an ideal candidate for drug development. However, now that a candidate inhibitor has been identified, the researchers will use the region on the DAPK molecule as a framework and employ fragment-based, structure-assisted drug design technology to create related, or analog, inhibitors with more desirable molecular properties.

Other researchers on this study were Anastasia V. Velentza, Mark S. Wainwright, Magdalena Zasadzki, Saalida Mirzoeva, Andrew M. Schumacher and Pamela J. Focia, Feinberg School of Medicine at Northwestern University; Jacques Haiech, Universite’ Louis Pasteur, Illkirch, France; and Martin Egli, Vanderbilt University, Nashville.