Proteasome Inhibitors for the Treatment of Stroke

Elliott, Peter

Abstract

Effective treatments for stroke and cerebral ischemia remain elusive. Strokes account for 10% of all premature deaths with a poor prognosis for surviving patients. The extent of the brain injury and the potential for its reversal depend upon the degree and duration of the ischemia. Infarcted tissue cannot be rescued; however, efforts to prevent additional damage represent the focus of novel treatments. The progression and extent of the injury is dependent upon the role of invasive neutrophils and cytotoxic and inflammatory cytokines, the expression of which are under control of the transcription factor, NF-kB. Activation of NF-kB results from proteolysis of its inhibitory protein, IkBa, via the intracellular ubiquitin-proteasome pathway. Proteasome inhibitors would block NF-kB activation and potentially reduce ischemic injury by attenuating the expression of many cytokines and adhesion molecules. To address the utility of proteasome inhibitors in stroke, we propose their testing in rodents using the nylon-filament middle cerebral artery occlusion method of ischemia. Preliminary in vitro and in vivo evidence is provided to support this hypothesis. Additional data from our Phase I research plan would be used to support development (Phase II) of such compounds as an intravenous therapy for post-stroke victims.

Proposed Commercial Applications

The aim of the proposal is the further understanding and utilization of the proteasome inhibitor PS-5 19, that significantly reduces ischemic brain injury. We would develop this compound into an effective drug for treating post- stroke victims. This drug and its analogs could also have therapeutic utility in other disorders, including brain and spinal cord injury, cerebrovascular vasospasm, myocardial ischemia, neointimal hyperplasia, neurotrauma and restenosis.