The ubiquitin-proteasome system as a drug target in cerebrovascular disease: therapeutic potential of proteasome inhibitors.

Proteasomes are large, multi-catalytic protease complexes that are found in the cytosol and in the nucleus of eukaryotic cells with a central role in cellular protein turnover. The ubiquitin-proteasome system (UPS) is the predominant non-lysosomal protein degradation pathway that ensures the viability, proliferation and signaling of eukaryotic organisms. Overwhelming data exist implicating a critical role for the UPS in cerebral ischemic injury. Ischemic and hypoxic trauma, and their associated oxidative, nitrosylative and energetic stress, underlie neurodegeneration following stroke, and evoke a discreet set of transcriptional events which have a complex and interdependent relationship with proteasomal function. Rapid elimination of denatured, misfolded and damaged proteins by the proteasome becomes a critical determinant of cell fate. Proof-of-principle has been obtained from animal models of cerebral ischemia, in which proteasome inhibitors reduce neuronal and astrocytic degeneration, cortical infarct volume, infarct neutrophil infiltration. and nuclear factor kappaB immunoreactivity. This neuroprotective efficacy has also been observed when proteasome inhibitors have been used 6 h after ischemic insult. Strategies aimed at effecting long-lasting changes in proteasomal function are not recommended, given the growing body of evidence implicating long-term proteasomal dysfunction in chronic neurodegenerative disease. These effects are likely due to the fact that the UPS is also essential for cellular growth, metabolism and repair, and untoward effects of proteasomal inhibition indicate that the development of short-lived proteasome inhibitors, or compounds which can spatially and temporally regulate the UPS, is a desirable clinical target. Studies in animal models indicate that the use of specific proteasome inhibitors may be beneficial in treating a host of acute neurological disorders, including ischemic stroke.