title: TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice.
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.
authors.affiliation: Department of Neurosurgery, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: King
authors.forename: Cargill H
authors.initials: CH
authors.lastname: Alleyne
authors.forename: Krishnan M
authors.initials: KM
authors.lastname: Dhandapani
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006406:Hematoma / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011810:Quinoxalines / Q000494:pharmacology* / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D011810:Quinoxalines; C582845:R-7050; D047888:Receptors, Tumor Necrosis Factor, Type I; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha