RT Journal Article
SR Electronic
T1 PTSD-Related Behavioral Traits in a Rat Model of Blast-Induced mTBI Are Reversed by the mGluR2/3 Receptor Antagonist BCI-838
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0357-17.2018
DO 10.1523/ENEURO.0357-17.2018
A1 Georgina Perez-Garcia
A1 Rita De Gasperi
A1 Miguel A. Gama Sosa
A1 Gissel M. Perez
A1 Alena Otero-Pagan
A1 Anna Tschiffely
A1 Richard M. McCarron
A1 Stephen T. Ahlers
A1 Gregory A. Elder
A1 Sam Gandy
YR 2018
UL http://www.eneuro.org/content/early/2018/01/29/ENEURO.0357-17.2018.abstract
AB Battlefield blast exposure related to improvised explosive devices has become the most common cause of traumatic brain injury (TBI) in the recent conflicts in Iraq and Afghanistan. Mental health problems are common after TBI. A striking feature in the most recent veterans has been the frequency with which mild TBI (mTBI) and post-traumatic stress disorder (PTSD) have appeared together, in contrast to the classical situations in which the presence of mTBI has excluded the diagnosis of PTSD. However, treatment of PTSD-related symptoms that follow blast injury has become a significant problem. BCI-838 (MGS0210) is a group II metabotropic glutamate receptor (mGluR2/3) antagonist prodrug and its active metabolite BCI-632 (MGS0039) has proneurogenic, procognitive and antidepressant activities in animal models. In humans, BCI-838 is currently in clinical trials for refractory depression and suicidality. This aim of the current study was to determine whether BCI-838 could modify the anxiety response and reverse PTSD-related behaviors in rats exposed to a series of low-level blast exposures designed to mimic a human mTBI or subclinical blast exposure. BCI-838 treatment reversed PTSD-related behavioral traits improving anxiety and fear-related behaviors as well as long-term recognition memory. Treatment with BCI-838 also increased neurogenesis in the dentate gyrus of blast-exposed rats. The safety profile of BCI-838 together with the therapeutic activities reported here, make BCI-838 a promising drug for the treatment of former battlefield Warfighters suffering from PTSD-related symptoms following blast-induced mTBI.Significance Statement Currently available therapies are only partially effective for the treatment of PTSD-related symptoms that appear following blast injury. Treatment with the proneurogenic mGluR2/3 receptor antagonist BCI-838 reversed PTSD-related behavioral traits in a rat model of blast-related mTBI. This study highlights BCI-838/BCI-632 and the mGluR2/3 pathway as potential leads in development of novel pharmacological therapies for PTSD-related symptoms that follow blast injury.