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

•R-7050, a novel TNFR antagonist, reduces neurovascular injury after ICH.•Pharmacological inhibition of TNFR improves outcomes after ICH.•TNFR may represent a viable therapeutic target after ICH. Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, exhibits the highest acute m...

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Bibliographic Details
Published in:Neuroscience letters 2013-05, Vol.542, p.92-96
Main Authors: King, Melanie D., Alleyne, Cargill H., Dhandapani, Krishnan M.
Format: Article
Language:English
Subjects:
Animals
Blood-Brain Barrier - metabolism
Blood–brain barrier
Brain - drug effects
Brain - metabolism
Brain - pathology
Brain Edema - drug therapy
Brain Edema - pathology
Cerebral Hemorrhage - drug therapy
Cerebral Hemorrhage - pathology
Cerebral Hemorrhage - physiopathology
Edema
Hematoma - drug therapy
Hematoma - pathology
Hemorrhage
Inflammation
Male
Mice
Neuroprotective Agents - pharmacology
Neuroprotective Agents - therapeutic use
Quinoxalines - pharmacology
Quinoxalines - therapeutic use
Receptors, Tumor Necrosis Factor, Type I - antagonists & inhibitors
Stroke
Triazoles - pharmacology
Triazoles - therapeutic use
Tumor Necrosis Factor-alpha - metabolism
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Summary:•R-7050, a novel TNFR antagonist, reduces neurovascular injury after ICH.•Pharmacological inhibition of TNFR improves outcomes after ICH.•TNFR may represent a viable therapeutic target after ICH. 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.
ISSN:0304-3940
1872-7972
DOI:10.1016/j.neulet.2013.02.051