, , , ,

By Brandon Lucke-Wold

Brandon Lucke-finalApproximately seven million concussions occur each year in the United States. Recent findings have shown that repetitive concussions can contribute to chronic neurodegeneration. Concussion patients, many of whom are athletes and soldiers, experience changes in mood and behavior triggered by the accumulation of tau neurofibrillary tangles. These tangles can lead to cell death within the brain.

We are investigating how blood-brain barrier disruption contributes to this progressive decline following traumatic brain injury. Our laboratory has developed and validated a replicable rodent blast traumatic brain injury model. Using this model, we have shown that blood-brain barrier disruption occurs early after injury and triggers damaging cascades in the brain. These cascades are the same ones we observe in human post-mortem samples from professional athletes. The blood-brain barrier acts as a wall between the brain and the rest of the body. This wall protects the brain from toxic molecules circulating in the blood. When the barrier is disrupted, the consequences for the brain can be devastating.

Micro RNAs have been shown to be acutely changed following concussion and to regulate the damaging cascades following blood-brain barrier disruption. We found that let7b, a micro RNA that controls toll-like receptors, was increased following blast traumatic brain injury. Let7b specifically controls toll like receptor 7, which has been linked to chronic neurodegeneration. Following blast exposure, the mice have robust cell death and show impulsive like behavior.

A new treatment however might prove promising in preventing this inevitable demise. Bryostatin is a protein kinase C modulator that is currently in clinical trials for Alzheimer disease. We administered bryostatin following blast exposure and found that it prevented blood-brain barrier disruption, decreased cell death, and provided enhanced neuroprotection. Because bryostatin has already been used to treat cancer and is in clinical trials for Alzheimer disease, it is reasonable that it may be efficacious for traumatic brain injury as well. We are currently looking at biomarkers for micro RNAs in serum samples from traumatic brain injury patients. This data will be correlated with the preclinical data to elucidate pharmacologic targets and optimal dosing for bryostatin. Protecting the integrity of the blood-brain barrier is essential for preventing progressive decline following concussions.

To find out about this study, visit this poster (#R6272) on Thursday, October 29, 2015, from 8:00 am–11:30 am ET in Exhibit Hall WA3 at the 2015 AAPS Annual Meeting and Exposition!

Brandon Lucke-Wold is an M.D./Ph.D. student at West Virginia University School of Medicine; the focus of his research is investigating novel pharmaceutical treatments for traumatic brain injury and stroke. He is supported by an American Medical Association Foundation Seed-Grant, an American Foundation of Pharmaceutical Education Pre-doctoral Fellowship, and a Neurosurgery Research and Education Foundation Medical Student Summer Research Fellowship.