title: Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice.
abstract: Hepatocyte growth factor (HGF), efficacious in preclinical models of acute central nervous system injury, is burdened by administration of full-length proteins. A multiinstitutional consortium investigated the efficacy of BB3, a small molecule with HGF-like activity that crosses the blood-brain barrier in rodent focal ischemic stroke using Stroke Therapy Academic Industry Roundtable (STAIR) and Good Laboratory Practice guidelines. In rats, BB3, begun 6 hours after temporary middle cerebral artery occlusion (tMCAO) reperfusion, or permanent middle cerebral artery occlusion (pMCAO) onset, and continued for 14 days consistently improved long-term neurologic function independent of sex, age, or laboratory. BB3 had little effect on cerebral infarct size and no effect on blood pressure. BB3 increased HGF receptor c-Met phosphorylation and synaptophysin expression in penumbral tissue consistent with a neurorestorative mechanism from HGF-like activity. In mouse tMCAO, BB3 starting 10 minutes after reperfusion and continued for 14 days improved neurologic function that persisted for 8 weeks in some, but not all measures. Study in animals with comorbidities and those exposed to common stroke drugs are the next steps to complete preclinical assessment. These data, generated in independent, masked, and rigorously controlled settings, are the first to suggest that the HGF pathway can potentially be harnessed by BB3 for neurologic benefit after ischemic stroke.
authors.affiliation: Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Rafael E
authors.initials: RE
authors.lastname: Chaparro
authors.affiliation: Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Miwa
authors.initials: M
authors.lastname: Izutsu
authors.affiliation: Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Sheng
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Homa
authors.initials: H
authors.lastname: Sadeghian
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Qin
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: von Bornstadt
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Fanny
authors.initials: F
authors.lastname: Herisson
authors.affiliation: Angion Biomedica Corporation, Uniondale, New York, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Duan
authors.affiliation: Angion Biomedica Corporation, Uniondale, New York, USA.
authors.forename: Jing-Song
authors.initials: JS
authors.lastname: Li
authors.affiliation: Angion Biomedica Corporation, Uniondale, New York, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Pearlstein
authors.affiliation: Department of Surgery, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Pearlstein
authors.affiliation: Angion Biomedica Corporation, Uniondale, New York, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Smith
authors.affiliation: Angion Biomedica Corporation, Uniondale, New York, USA.
authors.forename: Itzhak D
authors.initials: ID
authors.lastname: Goldberg
authors.affiliation: 1] Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA [2] Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
authors.affiliation: 1] Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina, USA [2] Department of Surgery, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina, USA [3] Department of Neurobiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D017228:Hepatocyte Growth Factor