Preventing Traumatic Brain Injury and Post-Traumatic Stress with High Dose Agomelatine – ProphyTraumAGO

Intervening in the “first golden” hours after a trauma is a pivotal factor in preventing its long-term consequences. The present proposal offers the possibility of determining whether a single prophylactic drug intake immediately after a major stress reduces the risks of behavioural and brain traumatic pathologies (NB: the proposal is not about treatment of these pathologies). Traumatic brain injuries (TBI) and post-traumatic stress disorder (PTSD) are often comorbid and associated with other anxio-depressive or cognitive disorders. In military or civilian settings, polytraumatisms is rather the rule than the exception, and we have in-hand validated translational rodent models to mimic ”double-” or “triple-” hit traumatic stresses. In these models we have successfully assessed TBI-induced neuroinflammation and epigenetically relevant microRNAs clinically known to be associated with the TBI/PTSD comorbidity.
We have good reasons to believe that acutely blocking 5-HT2 receptors while stimulating melatoninergic transmission has a prophylactic value. Acute traumas have profound disturbing effects on sleep and circadian rhythms that can be counteracted by helping the organism to cope with the stress during the first hours. Our preliminary results in mice show that a single high dose of a mixed melatoninergic agonist/ 5-HT2 antagonist, 1 hour after the last day of a series of social defeats prevents the social avoidance deficits, several days after its administration. To justify future clinical trials, we now need to assess the drug long-term effects in our transdisciplinary model of polytraumatism: first, behaviorally, by assessing PTSD-like fear memory, anxio-depressive, cognitive dysfunctions, and circadian rhythms (locomotion and body temperature), and second, biologically, by measuring relevant targets namely brain microglial activation, stress-ox enzymatic markers, mRNA coding for 5-HT2 receptors and its editing enzymes, micro-RNA biomarkers (such as miR-139-5p) in both blood and brain areas implicated in stress such as frontal cortex, hippocampus, amygdala.
The present project uses male and female animals in order to address both military (mostly men) and civilian (more often women) traumas. It aims to bring proof of concept evidence for the relevance of a single intervention with a repurposed compound as a prophylactic approach in trauma. Confirming our working hypothesis will be a first step towards early intervention. This will allow us to set forth efforts for clinical validation and a development strategy with clinical, defense, industry and institutional partners in the context of an ASTRID maturation project. A successful strategy has the potential of a major relief by reducing the long-term impact of physical but also “invisible wounds” for the millions of veterans, service members, first responders, and civilians who suffer from trauma-related conditions.