TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice

Neurosci Lett. 2013 May 10;542:92-6. doi: 10.1016/j.neulet.2013.02.051. Epub 2013 Mar 7.

Abstract

Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, exhibits the highest acute mortality and the worst long-term prognosis of all stroke subtypes. Unfortunately, treatment options for ICH are lacking due in part to a lack of feasible therapeutic targets. Inflammatory activation is associated with neurological deficits in pre-clinical ICH models and with patient deterioration after clinical ICH. In the present study, we tested the hypothesis that R-7050, a novel cell permeable triazoloquinoxaline inhibitor of the tumor necrosis factor receptor (TNFR) complex, attenuates neurovascular injury after ICH in mice. Up to 2h post-injury administration of R-7050 significantly reduced blood-brain barrier opening and attenuated edema development at 24h post-ICH. Neurological outcomes were also improved over the first 3 days after injury. In contrast, R-7050 did not reduce hematoma volume, suggesting the beneficial effects of TNFR inhibition were downstream of clot formation/resolution. These data suggest a potential clinical utility for TNFR antagonists as an adjunct therapy to reduce neurological injury and improve patient outcomes after ICH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / pathology
  • Brain Edema / drug therapy
  • Brain Edema / pathology
  • Cerebral Hemorrhage / drug therapy*
  • Cerebral Hemorrhage / pathology
  • Cerebral Hemorrhage / physiopathology
  • Hematoma / drug therapy
  • Hematoma / pathology
  • Male
  • Mice
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Quinoxalines / pharmacology*
  • Quinoxalines / therapeutic use
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors*
  • Triazoles / pharmacology*
  • Triazoles / therapeutic use
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Neuroprotective Agents
  • Quinoxalines
  • R-7050
  • Receptors, Tumor Necrosis Factor, Type I
  • Triazoles
  • Tumor Necrosis Factor-alpha