Neuroprotectant Therapeutic Interventions to Prevent Neurological Consequences in Combat Casualties
Abstract
Disturbances in blood flow to the brain and other organs sustained after trauma, heart attacks, and stroke trigger a process called ischemia and reperfusion injury (IRI) that results in substantial damage to human tissues. In addition to the damaging effects that lack of oxygen present to the brain and other organs, changes in blood chemistry and immune cell activation cause secondary damage to the brain, blood vessels, and other organs of the body once blood flow has been restored. This type of injury is commonly seen after cardiac arrest, stroke, and in the setting of military combat following blunt trauma and acute blood loss. Unfortunately, there are no agents currently available that can reduce the significant damage caused by IRI. Although discovered over 60 years ago as antibiotics, the tetracycline family of compounds also possesses both anti-inflammatory and tissue protective properties. Two members of this family, minocycline and doxycycline, have been well studied over the past 30 years for their anti-inflammatory activity in mammals. While both compounds have been shown experimentally to reduce brain and organ injury in a wide range of disease models, doxycycline is the only compound approved by the Food and Drug Administration for mitigating the enzymes found in tissue degradation and in particular ischemia and reperfusion-based pathologies. Furthermore, doxycycline is more stable for use under battlefield conditions, does not stain somatic tissues, and exhibits reduced cellular toxicity compared to minocycline. We have found that the doxycycline-based compound EBI-2114, developed in our lab, has excellent activity in blocking inflammation and tissue loss caused by IRI in both cell-based and animal models of stroke and cardiac arrest. We believe EBI-2114 serves as an ideal model compound from which to build the next generation of non-antibiotic tetracyclines to treat acute neurological injury. One of the key challenges in developing effective medicines to treat brain disorders involves optimizing their ability to cross the blood-brain barrier, which exists normally to protect the brain from foreign chemicals and immune attack. While doxycycline and minocycline have been used widely as antibiotics, little is known or reported on their ability to enter the brain, or what chemical features of the tetracyclines are responsible for their brain penetration. In this proposal, we seek to create and test a group of fourth-generation doxycycline derivatives using a battery of assays to identify compounds and chemical properties that are most beneficial. Aside from their ability to reduce neurological injury via effects on both nerve cells and reducing levels of inflammation, ideal compounds will also exhibit improved stability, lack of toxicity, and reduced or no anti-biotic activity against human bacteria to prevent the potential harmful effects of disturbing the normal flora in the host and promoting antibiotic resistance in the larger population. This grant will fund the discovery and biological study of more potent derivatives of doxycycline and EBI-2114 useful against brain trauma and the secondary effects of IRI. The compounds that will be synthesized will be novel, patentable, commercializable, and will fit a product profile that can be applied to treat IRI, particularly under battlefield or civilian population field and emergency conditions. While other approaches to reversing ischemic damage have been attempted during the history of modern medicine, to this day there are no compounds like EBI-2114 capable of treating the complex range of mechanisms that underlie this common condition.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610191
Entities
People
- Marc Halterman
Organizations
- United States Army
- University of Rochester