Pharmacology, Symes Lab
Symes Lab

THE PROBLEM

Traumatic brain injury (TBI)  is one of the most complex brain disorders to understand, and one of the most difficult to treat. Military personnel sustain TBIs more frequently than the general population from deployment and from training. Even mild TBIs or concussions can lead to chronic cognitive issues. More severe TBI may lead to long term neurologic impairment. All TBI increases the risk of later neurodegenerative diseases. Our current treatments are aimed at addressing the symptoms of brain injury, as we are not able to correct or repair the underlying deficits. In order to develop treatments for TBI we need to unravel the complex cascade of events that occur at different times after the initial impact. We will then be able to target specific processes to halt, reverse or repair the progression of harmful events.

OUR APPROACH

We focus on understanding the molecular signaling cascades that occur after TBI in addition to testing potential therapeutics to enhance recovery from injury. We currently utilize several different rodent models of traumatic brain injury (TBI), and determine functional outcomes after different treatments with behavioral assays that measure movement, memory, anxiety and awareness. We correlate behavior with changes in the cellular and molecular profile of different brain regions to fully assess the effects of the manipulations. In this way we are beginning to understand the complex interactions that occur after injury, and determine how targeted therapeutics impact functional recovery. We also utilize primary cell cultures to tease apart the molecular signaling pathways that contribute to inflammation and protection after injury.

Our Findings

We have shown that FDA approved drugs prescribed to people with hypertension are able to improve recovery in a mouse model of TBI. These drugs, called angiotensin receptor blockers, stop the signals from a protein that exacerbates many problematic processes after injury. After TBI, these drugs reduce inflammation and oxidative stress, enhance neuronal recovery, and increase cerebral blood flow. All of these effects result in better memory and improved movement after injury. As these drugs have minimal side effects and are already taken by millions of people, they should more easily be repurposed to treat patients with TBI.

A second related angiotensin pathway, that produces the peptide Angiotensin -(1-7), activates signals that should promote recovery after injury. Activation of this pathway is beneficial after stroke, and may also be beneficial after TBI. We have shown that drugs that activate this protective angiotensin pathway have similar effects to the angiotensin receptor blockers and can promote recovery in a mouse model of TBI. We are currently investigating both pathways, to determine the most efficacious drug for TBI.

Many cytokines become activated after injury and contribute to the inflammatory status of the brain. Although the inflammatory reaction is important for recovery initially, a chronic or prolonged inflammatory state ultimately proves problematic for many different aspects of recovery. The cytokine TGF-beta is induced after injury, and can influence every cell type in the brain in different ways. We have shown that blocking an important TGF-beta activated signaling pathway, actually enhances the glial reaction to injury, so that the wound heals quicker. However, we also found that this process is harmful to neurons, as more neurons die after injury when this signaling is prevented. These experiments show the complexity of signaling pathways after injury, such that one process can have opposite effects in different cells. We therefore are working on more targeted approaches.

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