Proteasomal inhibition in intracerebral hemorrhage: neuroprotective and anti-inflammatory effects of bortezomib.
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.
Sinn
Dong-In
DI
Stroke & Neural Stem Cell Laboratory in Clinical Research Institute, Department of Neurology, Seoul National University Hospital, Program in Neuroscience, Neuroscience Research Institute of SNUMRC, Seoul National University, Seoul, South Korea.
Lee
Soon-Tae
ST
Chu
Kon
K
Jung
Keun-Hwa
KH
Kim
Eun-Hee
EH
Kim
Jeong-Min
JM
Park
Dong-Kyu
DK
Song
Eun-Cheol
EC
Kim
Byung-Su
BS
Yoon
Sung-Soo
SS
Kim
Manho
M
Roh
Jae-Kyu
JK
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D005911:Gliosis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D001897:Boronic Acids; D016207:Cytokines; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D011480:Protease Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex