Metalloporphyrins as therapeutic catalytic oxidoreductants in central nervous system disorders.

Abstract

Significance

Metalloporphyrins, characterized by a redox-active transitional metal (Mn or Fe) coordinated to a cyclic porphyrin core ligand, mitigate oxidative/nitrosative stress in biological systems. Side-chain substitutions tune redox properties of metalloporphyrins to act as potent superoxide dismutase mimics, peroxynitrite decomposition catalysts, and redox regulators of transcription factor function. With oxidative/nitrosative stress central to pathogenesis of CNS injury, metalloporphyrins offer unique pharmacologic activity to improve the course of disease.

Recent advances

Metalloporphyrins are efficacious in models of amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, neuropathic pain, opioid tolerance, Parkinson's disease, spinal cord injury, and stroke and have proved to be useful tools in defining roles of superoxide, nitric oxide, and peroxynitrite in disease progression. The most substantive recent advance has been the synthesis of lipophilic metalloporphyrins offering improved blood-brain barrier penetration to allow intravenous, subcutaneous, or oral treatment.

Critical issues

Insufficient preclinical data have accumulated to enable clinical development of metalloporphyrins for any single indication. An improved definition of mechanisms of action will facilitate preclinical modeling to define and validate optimal dosing strategies to enable appropriate clinical trial design. Due to previous failures of "antioxidants" in clinical trials, with most having markedly less biologic activity and bioavailability than current-generation metalloporphyrins, a stigma against antioxidants has discouraged the development of metalloporphyrins as CNS therapeutics, despite the consistent definition of efficacy in a wide array of CNS disorders.

Future directions

Further definition of the metalloporphyrin mechanism of action, side-by-side comparison with "failed" antioxidants, and intense effort to optimize therapeutic dosing strategies are required to inform and encourage clinical trial design.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1089/ars.2013.5413

Publication Info

Sheng, Huaxin, Raphael E Chaparro, Toshihiro Sasaki, Miwa Izutsu, Robert D Pearlstein, Artak Tovmasyan and David S Warner (2014). Metalloporphyrins as therapeutic catalytic oxidoreductants in central nervous system disorders. Antioxidants & redox signaling, 20(15). pp. 2437–2464. 10.1089/ars.2013.5413 Retrieved from https://hdl.handle.net/10161/23274.

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Scholars@Duke

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.

Chaparro

Eduardo Chaparro

Research Scholar

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.


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