Defense Medical Research and Development
Identification and Validation of Novel Therapeutic Targets for Traumatic Brain Injury
Posted August 24, 2016
Fiona Crawford, Ph.D., Roskamp Institute
Mild traumatic brain injury (mTBI) is of increasing concern for the Warfighter; approximately 266,000 military Service members suffered mTBIs between the years 2000-2012. Even though mTBIs constitute approximately 80% of all TBIs, there is little known about the etiology, prognosis, and long-term effects of mTBI. With support from a JPC-6 FY09 Investigator-Initiated Research Award, Dr. Fiona Crawford from the Roskamp Institute in Sarasota, Florida was among the first to develop a mouse model of repetitive mTBI. Dr. Crawford and her team took steps in developing the model to ensure that it closely mimicked human mTBI. In addition to developing the model, the team conducted neurobehavioral and neuropathological examinations of their repetitive injury model at extended time points post-injury.
The data generated by the Roskamp team has been instrumental in characterizing the long-term consequences of mTBI, as the mice were injured at 2-3 months of age and then analyzed over a 24 month period after injury – essentially the mouse lifespan. Notably, repetitively injured mice have persistent cognitive deficits when compared to singly injured mice or controls throughout the lifespan, and progressive inflammation as evidenced by microgliosis and astrogliosis, particularly in the corpus callosum. Specifically, electron microscopic analysis of the repetitively injured mice revealed ultrastructural changes in white and grey matter. The researchers found white matter damage typified by axonal degeneration, microglial phagocytosis, and increased neuroglial cell density. In the cortex of repetitively injured mice, there was evidence of synaptic degeneration, dark neurons, altered dendritic microfilaments, subtle changes to the microvasculature, a mild augmentation of age-related features such as lipofuscin deposition, and electron dense inclusions in microglial and perivascular cells. Taken together, these degenerative changes are indicative of cognitive decline and could help explain the mechanisms behind cognitive dysfunctions in humans following mTBI.
Furthermore, the researchers noted significant visual function deficits and increased neuroinflammation in repetitively injured mice in the weeks following the repetitive mTBI. An overall decrease in optic nerve diameter, increased cellularity, and areas of demyelination were clearly detectable in optic nerves of repetitively injured mice but were not visible in the control mice. Together with emerging clinical observations, these findings emphasize the possibility of a profound and lasting visual dysfunction, particularly after repetitive mild injury, occurring over a relatively short interval. This has considerable implications and relevance in deployment-related mTBI, as well as civilian and sport-related-TBIs, where repeated mTBIs can occur in a short span of time.
The Roskamp model was able to successfully recapitulate many of the features of human TBI such as white matter degeneration, visual dysfunction, and neuroinflammation. Contrary to their initial hypothesis, the researchers found no significant differences in any tau immunohistochemical measures between injured mice and control mice. Further experiments using transgenic hTau mice revealed age-dependent, but not injury-dependent changes in tau. Currently, Dr. Crawford is investigating potential targets and therapeutics for mTBI and has promising data that indicates the alkaloid anatabine can decrease neuroinflammation and improve cognition in their model of repetitive mTBI. Future studies will characterize the treatment window, the time course of treatment needed, and the dose needed to achieve therapeutic levels of anatabine in humans after injury.
Last updated Tuesday, October 13, 2020