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

Neurosci Res. 2007 May;58(1):12-8. doi: 10.1016/j.neures.2007.01.006. Epub 2007 Jan 19.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Biomarkers / analysis
  • Biomarkers / metabolism
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Brain Edema / drug therapy
  • Brain Edema / etiology
  • Brain Edema / physiopathology
  • Cerebral Cortex / blood supply
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / physiopathology
  • Cerebral Hemorrhage / complications
  • Cerebral Hemorrhage / drug therapy*
  • Cerebral Hemorrhage / physiopathology
  • Cytokines / antagonists & inhibitors
  • Cytokines / genetics
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Encephalitis / drug therapy*
  • Encephalitis / etiology
  • Encephalitis / physiopathology
  • Gliosis / drug therapy
  • Gliosis / etiology
  • Gliosis / physiopathology
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Male
  • Microglia / drug effects
  • Microglia / immunology
  • Microglia / metabolism
  • Neuroprotective Agents / pharmacology
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Protease Inhibitors / pharmacology*
  • Proteasome Endopeptidase Complex / drug effects*
  • Proteasome Endopeptidase Complex / metabolism
  • Pyrazines / pharmacology*
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Treatment Outcome

Substances

  • Anti-Inflammatory Agents
  • Biomarkers
  • Boronic Acids
  • Cytokines
  • Inflammation Mediators
  • Neuroprotective Agents
  • Protease Inhibitors
  • Pyrazines
  • RNA, Messenger
  • Bortezomib
  • Proteasome Endopeptidase Complex