Ubiquitin-proteasome system and proteasome inhibition: new strategies in stroke therapy.
OBJECTIVE
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.


RESULTS
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.
Wojcik
Cezary
C
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Di Napoli
Mario
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology; D002490:Central Nervous System / Q000201:enzymology; D003546:Cysteine Endopeptidases / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D000860:Hypoxia / Q000201:enzymology; D007249:Inflammation / Q000201:enzymology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000502:physiology
D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D016328:NF-kappa B; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D014452:Ubiquitins; D000255:Adenosine Triphosphate; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex