Valproic Acid Treatment Rescues Injured Tissues After Traumatic Brain Injury

BACKGROUND No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate pro-survival pathways. METHODS Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously over 1 hour; n=4) or control (saline vehicle; n=4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry (MS) imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers, and subjected to proteomic and pathway analysis. RESULTS Brain lesion size was 50% smaller (p=0.01) in the VPA treated animals (3837±948 mm) compared to the controls (1900±614 mm). Endothelial regions had 8-fold higher VPA concentrations than perivascular regions by MS-imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared to the control animals (p<0.05). Over 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism and biosynthetic machinery. CONCLUSIONS VPA penetrates injured brain tissues, and exerts neuroprotective and pro-survival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies. LEVEL OF EVIDENCE Not applicable; basic science.