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Proteasomal inhibition in intracerebral hemorrhage: neuroprotective and anti-inflammatory effects of bortezomib
Cited 35 time in
Web of Science
Cited 39 time in Scopus
- Authors
- Issue Date
- 2007-03-03
- Publisher
- Elsevier
- Citation
- Neurosci Res. 2007 May;58(1):12-8. Epub 2007 Jan 19.
- Keywords
- Animals ; Anti-Inflammatory Agents/pharmacology ; Biological Markers/analysis/metabolism ; Boronic Acids/*pharmacology ; Brain Edema/drug therapy/etiology/physiopathology ; Cerebral Cortex/blood supply/*drug effects/physiopathology ; Cerebral Hemorrhage/complications/*drug therapy/physiopathology ; Cytokines/antagonists & inhibitors/genetics ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Encephalitis/*drug therapy/etiology/physiopathology ; Gliosis/drug therapy/etiology/physiopathology ; Inflammation Mediators/antagonists & inhibitors/metabolism ; Male ; Microglia/drug effects/immunology/metabolism ; Neuroprotective Agents/pharmacology ; Neutrophils/drug effects/immunology/metabolism ; Protease Inhibitors/*pharmacology ; Proteasome Endopeptidase Complex/*drug effects/metabolism ; Pyrazines/*pharmacology ; RNA, Messenger/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Treatment Outcome
- Abstract
- Inflammation is an important pathophysiologic mechanism of injury induced by intracerebral hemorrhage (ICH). The ubiquitin-proteasome system (UPS) regulates the inflammatory responses via the up-regulation of several pro-inflammatory molecules. In this study, we determined that a potent proteasome inhibitor, bortezomib, exerted therapeutic effects in experimental model of ICH. Either bortezomib (0.05, 0.2, 0.5, 1mg/kg) or vehicle was intravenously administered 2h after ICH induction. The high doses of bortezomib caused high mortality rates. Bortezomib at 0.2 mg/kg reduced the early hematoma growth and alleviated hematoma volume and brain edema at 3 days after ICH, compared with the ICH-vehicle group. The numbers of myeloperoxidase(+) neutrophils, Ox42(+) microglia, and TUNEL(+) cells in the perihematomal regions were decreased by bortezomib. Bortezomib induced significant decrements of mRNA expression of TNF-alpha and IL-6. The production of iNOS and COX2 was also reduced significantly by bortezomib. We concluded that the early treatment with bortezomib induced a reduction in the early hematoma growth and mitigated the development of brain edema, coupled with a marked inhibitory effect on inflammation in ICH.
- ISSN
- 0168-0102 (Print)
- Language
- English
- URI
- http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T0H-4MVN0VG-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=d8af336df0b6995eabcb98d1713c882d
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17328981
https://hdl.handle.net/10371/22326
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