Traumatic brain injury (TBI) is a major public health problem, with over 1.7 million new cases occurring each year in the United States alone. Axons are the cellular components most at risk in TBI. While there is currently no effective treatment for axonal injury in head injured patients, laboratory experiments using rodent models of TBI show the immunosuppressant drugs Cyclosporin-A and FK506 as beneficial in improving the structure and function of axons when applied as treatments following TBI. This project investigates a novel use for the antibiotic Clofazimine (CFZ) as a neuroprotectant to improve outcome following TBI. The research objectives of the project build on exciting new evidence that CFZ improves the properties of compound action potentials (CAPs) evoked in corpus callosum axons, following an experimental TBI in adult rats. CFZ mimics the neuroprotective properties, but lacks the nephrotoxic side effects, of Cyclosporin-A and FK506. In this way it may have more potential as a treatment which may ultimately translate to clinical usage. The goals of this project are to 1) determine the ultrastructural and molecular changes which accompany CFZ benefits observed for evoked axonal CAPs;2) explore the glial role (microglia, astrocytes, oligodendrocytes) in CFZ neuroprotection;and, 3) investigate the efficacy of CFZ to improve performance in working memory, spatial cognition, and neurological behavior after TBI. The long-term goal is to translate findings from these laboratory studies to the development of therapeutic strategies to improve white matter functioning specifically, and outcome of TBI generally, in human patients.

Public Health Relevance

Although traumatic brain injury (TBI) is a complex pathology, affecting multiple brain regions and cell types, axons are especially vulnerable to this pathology. This project uses a rodent model of TBI to evaluate a therapy based on inhibition of specific ion channels, and tests a compound for efficacy to reduce axonal injury. The findings of the project will provide clinically relevant information regarding therapeutic strategies to treat human TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057758-07
Application #
8609079
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2006-12-01
Project End
2017-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
7
Fiscal Year
2014
Total Cost
$297,134
Indirect Cost
$100,259
Name
Virginia Commonwealth University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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