Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice.
Date
2015-06
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
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.
Type
Department
Description
Provenance
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Chaparro, Rafael E, Miwa Izutsu, Toshihiro Sasaki, Huaxin Sheng, Yi Zheng, Homa Sadeghian, Tao Qin, Daniel von Bornstadt, et al. (2015). Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 35(6). pp. 1044–1053. 10.1038/jcbfm.2015.23 Retrieved from https://hdl.handle.net/10161/23268.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Scholars@Duke
Eduardo Chaparro
Dr. Chaparro earned his Medical Doctorate from Javeriana University in Bogotá, Colombia, and his Ph.D. in Medical Sciences with a specialization in Physiology, Pharmacology, and Neuroscience from the University of South Florida (USF) in Tampa, Florida. During his graduate studies at USF’s Anesthesiology Department, he investigated the effects of anesthetics and anti-apoptotic compounds on brain ischemia.
Following the completion of his Ph.D., Dr. Chaparro pursued post-doctoral training at Duke University’s Multidisciplinary Neuroprotection Laboratory. Here, he focused on testing drugs and devices in various animal models of neurological conditions. His work received special recognition for the successful testing of the first hepatocyte growth factor mimetic in an animal model of transient cerebral ischemia. Additionally, he successfully tested an FDA-approved vestibular stimulator for human use.
Dr. Chaparro then joined the Cerebrovascular and Skull Base Division at Duke University’s Department of Neurosurgery. His research has been dedicated to developing treatments for neurovascular conditions such as stroke, moyamoya disease, aneurysms, intracerebral hemorrhages, intravascular stent thrombogenicity, traumatic brain injury, and epilepsy. He currently serves as the Director of the Neurovascular Laboratory.
An entrepreneur at heart, Dr. Chaparro’s interest in hypothermia as a treatment for neuronal inflammation led him to patent a brain-cooling device, which has been successfully tested in non-human primates. He founded Neurocool, a startup aimed at further developing this prototype. As Medical Director, he is working towards FDA approval and the development of a human-compatible device to aid patients with central nervous system inflammatory conditions.
Huaxin Sheng
We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction. Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral ischemia and the other is to examine the efficacy of post-conditioning on outcome of subarachnoid hemorrhage induced cognitive dysfunction.
Robert D. Pearlstein
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.