Proteasomal inhibition in intracerebral hemorrhage: Neuroprotective and anti-inflammatory effects of bortezomib.
Neurosci Res. 2007 Jan 19;
Sinn DI, Lee ST, Chu K, Jung KH, Kim EH, Kim JM, Park DK, Song EC, Kim BS, Yoon SS, Kim M, Roh JK.
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.
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 0.2mg/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. |
