Boldine treatment prevents chronic cognitive impairment and exaggerated fear learning in rats exposed to repetitive low-level blast injury.

Many Veterans who experienced blast-related traumatic brain injuries (TBI) during their military service suffer from chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast injuries designed to mimic the type of blast-related mild TBI that was so common in the conflicts in Iraq and Afghanistan develop delayed and persistent cognitive and PTSD-related traits that remain present for over 1 year after exposure. Boldine, an alkaloid derived from the Chilean Boldo tree (Peumus boldus), is a widely used herbal remedy with anti-oxidant, anti-inflammatory, hepatoprotective, and connexin hemichannel-blocking properties. We studied whether oral administration of boldine prevented development of PTSD-related behavioral traits in rats exposed to repetitive low-level blast. Treatment with boldine prevented appearance of the blast-induced PTSD-like phenotype including object recognition deficits and exaggerated cued fear learning. Boldine also prevented blast-induced elevation of the metabotropic glutamate receptor 2 (mGluR2) and the N-methyl-D-aspartate receptor 2b (NMDAR2b), but did not reverse decreases in the serotonin 5-HT2A receptor. Iba1 immunofluorescence staining suggested that boldine reduced blast-associated microglial process retraction (indicative of activation) in the somatosensory cortex. Transcriptomics analysis of hippocampus mRNA did not identify individual genes that remained significant after FDR correction. Exploratory analysis of 85 nominally significant candidates suggested that boldine induced coordinated transcriptional changes related to GO terms "Cognition" and "Neurotransmitter Transport," consistent with modulation of activity-regulated transcription factors and neuroimmune signaling. These studies suggest that boldine may be beneficial for the neurobehavioral syndromes that follow blast exposure in military Veterans.