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Proteasomal inhibition in intracerebral hemorrhage: neuroprotective and anti-inflammatory effects of bortezomib

Cited 33 time in Web of Science Cited 36 time in Scopus
Authors
Sinn, Dong-In; Lee, Soon-Tae; Chu, Kon; Jung, Keun-Hwa; Kim, Eun-Hee; Kim, Jeong-Min; Park, Dong-Kyu; Song, Eun-Cheol; Kim, Byung-Su; Yoon, Sung-Soo; Kim, Manho; Roh, Jae-Kyu
Issue Date
2007
Publisher
Elsevier
Citation
Neurosci. Res. 58, 12-18
Keywords
AnimalsAnti-Inflammatory Agents/pharmacologyBiological Markers/analysis/metabolismBoronic Acids/*pharmacologyBrain Edema/drug therapy/etiology/physiopathologyCerebral Cortex/blood supply/*drug effects/physiopathologyCerebral Hemorrhage/complications/*drug therapy/physiopathologyCytokines/antagonists & inhibitors/geneticsDisease Models, AnimalDose-Response Relationship, DrugEncephalitis/*drug therapy/etiology/physiopathologyGliosis/drug therapy/etiology/physiopathologyInflammation Mediators/antagonists & inhibitors/metabolismMaleMicroglia/drug effects/immunology/metabolismNeuroprotective Agents/pharmacologyNeutrophils/drug effects/immunology/metabolismProtease Inhibitors/*pharmacologyProteasome Endopeptidase Complex/*drug effects/metabolismPyrazines/*pharmacologyRNA, Messenger/drug effects/metabolismRatsRats, Sprague-DawleyTreatment 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.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17328981

http://hdl.handle.net/10371/25597
DOI
https://doi.org/10.1016/j.neures.2007.01.006
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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