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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology
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Biomarkers / analysis
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Biomarkers / metabolism
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Boronic Acids / pharmacology*
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Bortezomib
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Brain Edema / drug therapy
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Brain Edema / etiology
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Brain Edema / physiopathology
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Cerebral Cortex / blood supply
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Cerebral Cortex / drug effects*
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Cerebral Cortex / physiopathology
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Cerebral Hemorrhage / complications
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Cerebral Hemorrhage / drug therapy*
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Cerebral Hemorrhage / physiopathology
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Cytokines / antagonists & inhibitors
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Cytokines / genetics
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Encephalitis / drug therapy*
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Encephalitis / etiology
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Encephalitis / physiopathology
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Gliosis / drug therapy
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Gliosis / etiology
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Gliosis / physiopathology
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Inflammation Mediators / antagonists & inhibitors
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Inflammation Mediators / metabolism
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Male
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Microglia / drug effects
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Microglia / immunology
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Microglia / metabolism
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Neuroprotective Agents / pharmacology
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Neutrophils / drug effects
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Neutrophils / immunology
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Neutrophils / metabolism
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Protease Inhibitors / pharmacology*
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Proteasome Endopeptidase Complex / drug effects*
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Proteasome Endopeptidase Complex / metabolism
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Pyrazines / pharmacology*
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Treatment Outcome
Substances
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Anti-Inflammatory Agents
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Biomarkers
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Boronic Acids
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Cytokines
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Inflammation Mediators
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Neuroprotective Agents
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Protease Inhibitors
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Pyrazines
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RNA, Messenger
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Bortezomib
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Proteasome Endopeptidase Complex