Published Online
on April 29, 2004

A more recent version of this article appeared on June 1, 2004

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Submitted on October 14, 2003
Revised on December 31, 2003
Accepted on February 9, 2004

Ubiquitin-Proteasome System and Proteasome Inhibition: New Strategies in Stroke Therapy

Cezary Wojcik MD, PhD, DSc and Mario Di Napoli MD^*

From the Department of Physiology (C.W.), University of Texas Southwestern Medical Center, Dallas, TX; and Neurological Section (M.D.N.), SMDN-Center for Cardiovascular Medicine and Cerebrovascular Disease Prevention, Sulmona (L’Aquila), Italy.

^* To whom correspondence should be addressed. E-mail: mariodinapoli{at}katamail.com.

Background and Purpose--Proteasomes are large multicatalytic proteinase 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) has a central role in the selective degradation of intracellular proteins. Among the key proteins whose levels are modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. There are now overwhelming data suggesting that the UPS contributes to cerebral ischemic injury.

Summary of Review--Proteasome inhibition is a potential treatment option for stroke. Thus far, proof of principle has been obtained from studies in several animal models of cerebral ischemia. Treatment with proteasome inhibitors reduces effectively neuronal and astrocytic degeneration, cortical infarct volume, infarct neutrophil infiltration, and NF-B immunoreactivity with an extension of the neuroprotective effect at least 6 hours after ischemic insult. However, it is clear that the UPS represents a central pathway for the processing and metabolism of multiple proteins with critical roles in cellular function. To avoid eliciting significant side effects associated with complete inhibition of the proteasome and the possible immunosuppressive effects from persistent suppression of NF-B activation, it is critical that we understand how to partially and temporally attenuate proteasome function to elicit the desired therapeutic effect before any large-scale use in humans.

Conclusion--This review highlights the most recent advances in our knowledge on UPS, as well as the early experience of using proteasome inhibition strategies to treat acute stroke.

Key words: cerebral ischemia • NF-kappa B • inflammation • ubiquitin • proteasome

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