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.
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.
|Schurman, Lesley D; Smith, Terry L; Morales, Anthony J et al. (2017) Investigation of left and right lateral fluid percussion injury in C57BL6/J mice: In vivo functional consequences. Neurosci Lett 653:31-38|
|Reeves, Thomas M; Trimmer, Patricia A; Colley, Beverly S et al. (2016) Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury. Exp Neurol 283:188-203|
|Sato, Masatoshi; Sagawa, Yohei; Hirai, Nobuhide et al. (2014) Noninvasive detection of sleep/wake changes and cataplexy-like behaviors in orexin/ataxin-3 transgenic narcoleptic mice across the disease onset. Exp Neurol 261:744-51|
|Phillips, Linda L; Chan, Julie L; Doperalski, Adele E et al. (2014) Time dependent integration of matrix metalloproteinases and their targeted substrates directs axonal sprouting and synaptogenesis following central nervous system injury. Neural Regen Res 9:362-76|
|Chan, Julie L; Reeves, Thomas M; Phillips, Linda L (2014) Osteopontin expression in acute immune response mediates hippocampal synaptogenesis and adaptive outcome following cortical brain injury. Exp Neurol 261:757-71|
|Hait, Nitai C; Wise, Laura E; Allegood, Jeremy C et al. (2014) Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat Neurosci 17:971-80|
|Reeves, Thomas M; Smith, Terry L; Williamson, Judy C et al. (2012) Unmyelinated axons show selective rostrocaudal pathology in the corpus callosum after traumatic brain injury. J Neuropathol Exp Neurol 71:198-210|
|Warren, Kelly M; Reeves, Thomas M; Phillips, Linda L (2012) MT5-MMP, ADAM-10, and N-cadherin act in concert to facilitate synapse reorganization after traumatic brain injury. J Neurotrauma 29:1922-40|
|Harris, Janna L; Reeves, Thomas M; Phillips, Linda L (2011) Phosphacan and receptor protein tyrosine phosphatase ýý expression mediates deafferentation-induced synaptogenesis. Hippocampus 21:81-92|
|Reeves, Thomas M; Greer, John E; Vanderveer, Andrew S et al. (2010) Proteolysis of submembrane cytoskeletal proteins ankyrin-G and ?II-spectrin following diffuse brain injury: a role in white matter vulnerability at Nodes of Ranvier. Brain Pathol 20:1055-68|
Showing the most recent 10 out of 12 publications