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.

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Citation

Published Version (Please cite this version)

10.1038/jcbfm.2015.23

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.

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Scholars@Duke

Eduardo Chaparro

Research Scholar

Dr. Chaparro received his Medical Doctoral degree from Javeriana University in Bogota - Colombia and his Ph.D. in Medical Sciences with a focus on Physiology, Pharmacology, and Neuroscience from the University of South Florida in Tampa - Florida. He joined the Anesthesiology Department at USF for his graduate work to study the effects of anesthetics and anti-apoptotic compounds in brain ischemia. After completing his Ph.D., he came to Duke University for his post-doctoral training at the Multidisciplinary Neuroprotection Laboratory where he dedicated his time to testing drugs and devices in different animal models of neurological conditions getting special recognition for successfully testing the first hepatocyte growth factor mimetic in an animal model of transient cerebral ischemia. He also successfully tested a vestibular stimulator approved by the FDA for human use. After completing his post-doctoral training, Dr. Chaparro joined the Cerebrovascular and Skull Base Division at the Duke University Department of Neurosurgery where he has dedicated his career to testing treatments for neurovascular conditions including stroke, moyamoya disease, aneurysms, intra-cerebral hemorrhages, intravascular stent thrombogenicity, traumatic brain injury, and epilepsy. Dr. Chaparro is also an entrepreneur, and his interest in hypothermia as a treatment for neuronal inflammation, let him patent a brain-cooling device that has been successfully tested in non-human primates. He assembles a team of engineers, neuroscientists, and business experts to create Neurocool, a startup to develop the prototype further. As a CEO he is working on getting FDA approval and developing a human-compatible device aiming to help patients with central nervous system inflammatory conditions.

Sheng

Huaxin Sheng

Associate Professor in Anesthesiology

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

Assistant Professor Emeritus in Neurosurgery

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