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

2004/05/04 by Cezary Wojcik, Cezary Wójcik, Mario Di Napoli · 140 citations
Biochemistry, Genetics and Molecular Biology · Medicine · Neuroscience · #Biochemistry #Biology #Cell biology #Cerebrovascular and genetic disorders #Clusterin in disease pathology #Gene #Internal medicine #Intracellular #Ischemia #Medicine #Neuroprotection #Neuroscience #Pharmacology #Proteasome #Proteasome inhibitor #Protein biosynthesis #Protein degradation #Protein turnover #Ubiquitin #Ubiquitin and proteasome pathways

paper · doi:10.1161/01.str.0000126891.93919.4e

published in Stroke 35(6), 1506-1518 (Lippincott Williams & Wilkins)

openalex publication_date 2004/05/04 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28

Abstract

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-kappaB 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-kappaB 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. CONCLUSIONS: 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.

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