title: Systemic hemin therapy attenuates blood-brain barrier disruption after intracerebral hemorrhage.
abstract: Injury to the blood-brain barrier (BBB) is a key feature of intracerebral hemorrhage (ICH) and may contribute to perihematomal cell injury. Pretreatment with the heme oxygenase (HO)-1 inducer hemin improves barrier function and neurological outcome in experimental models of traumatic and ischemic CNS injury. Since hemin is already in clinical use to treat acute porphyrias, this translational study was designed to test its effect on BBB function when initiated after ICH in two mouse models. At a dose similar to those used in most preconditioning studies (26mg/kg i.p.), post-hemorrhage treatment with hemin reduced parenchymal extravasation of Evans blue by about three-quarters in both the blood injection and collagenase ICH models. Similar efficacy was observed when treatment was begun at 1 or 3h. At the lower dose that is currently in clinical use (4mg/kg beginning at 3h), hemin also improved barrier function in both models, as assessed by both Evans blue and FITC-dextran leakage; however, it was somewhat less potent, reducing Evans blue leakage by about half. This dose was nevertheless sufficient to attenuate striatal cell loss and accelerate neurological recovery. Consistent with prior observations, striatal HO-1 expression was increased by hemin, and was localized to perivascular cells. These results suggest that hemin may be an effective therapy for ICH with a clinically relevant time window. Further study of the repurposing of this old drug seems warranted.
authors: Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107, United States.
authors: Xiangping
authors: X
authors: Lu
authors: Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107, United States.
authors: Jing
authors: J
authors: Chen-Roetling
authors: Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107, United States. Electronic address: Raymond.Regan@jefferson.edu.
authors: Raymond F
authors: RF
authors: Regan
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003342:Corpus Striatum / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D008565:Membrane Proteins; D018696:Neuroprotective Agents; D006427:Hemin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Heme; Heme oxygenase; Preconditioning; Stroke