Traumatic Brain Injury and Neuroinflammation

Traumatic brain injury (TBI) is one of the major public health and socioeconomic problems in both developed and developing countries.  In the United States alone, an estimated 1.7 million civilians sustain TBI each year.  Most TBI cases (70–90%) are classified as mild TBI, which is generally considered synonymous with concussion.  In the military, it has been estimated that 5–35% of American service members deployed to Iraq and Afghanistan sustained a concussion, with 80% of these injuries being secondary to blast exposures.

Whether it is severe brain trauma or concussion, the survival and neurological recovery of patients who have sustained TBI largely depends on the extent of post-traumatic neuroinflammation (Zink et al., 2010, Szmydynger-Chodobska et al., 2016).  Our research suggests that in both severe TBI and concussion, targeting neuroinflammation can have beneficial effects on neuronal survival and long-term cognitive recovery after injury.  Unfortunately, many neuroprotective interventions showing therapeutic potential in preclinical studies have failed to demonstrate consistent improvement of outcome in TBI patients.  One reason for this failure of clinical trials is the complex nature of pathophysiological events resulting from neurotrauma.  Another problem associated with translation of preclinical studies into clinical practice is that the time-window for some experimental interventions may be too short to achieve significant therapeutic efficacy in the clinical setting.

Concussion also represents a significant diagnostic challenge.  The diagnosis is frequently subjective, based on self-reported neurological symptoms, which could be ignored or overstated.  Accordingly, there has been a considerable interest in identifying blood biomarkers that could allow for the objective diagnosis of concussion.  Our laboratory was successful in identifying a panel of blood biomarkers that allow for the diagnosis of concussion with 90% accuracy in adult patients (Shan et al., 2016).

Another important factor central to the progression of post-traumatic neuroinflammation is dysfunction of the blood-brain-barrier (BBB) observed after injury. Brain endothelium itself can be an important source of proinflammatory mediators, such as neutrophil and monocyte chemoattractants. Increased production of chemokines and augmented expression of cell adhesion molecules on the surface of cerebrovascular endothelium promote invasion of inflammatory cells with detrimental consequences to the integrity of neural tissue. Our laboratory has demonstrated that AVP contributes to dysfunction of the BBB by amplifying the synthesis of proinflammatory mediators and, consequently, promoting the invasion of inflammatory cells.

Ongoing Studies

Using the controlled cortical impact model of TBI in rats, we are currently evaluating the therapeutic efficacy of two novel multifunctional biologics: PRG4 and CN2097.  These two drug candidates exert anti-inflammatory therapeutic effects and are expected to produce the long-term improvement in cognitive function.  If successful, these translational studies could open up new avenues for treatment of TBI patients.

Another ongoing project in the lab is focused on enhancing our understanding of pathological mechanisms associated with repetitive concussions.  We want to find out whether there is a “safe” time between consecutive injuries and why repetitive concussions may lead to neurodegenerative diseases later in life.

If you would like to learn more about our research or become involved in our projects, please call at -401-444-4285 or contact us via e-mail at [email protected] or [email protected]