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Early treatment with valproic acid (VPA) has demonstrated benefit in preclinical models of traumatic brain injury, including smaller brain lesion size, decreased edema, reduced neurologic disability, and faster recovery. Mechanisms underlying these favorable outcomes are not fully understood. We hypothesized that VPA treatment would upregulate genes involved in cell survival and proliferation and downregulate those associated with cell death and the inflammatory response.Ten female swine were subjected to a protocol of traumatic brain injury and hemorrhagic shock. They were assigned to two groups (n = 5): normal saline (NS; 3× volume of shed blood), or NS + VPA (150 mg/kg). Following 6 hours of observation, brain tissue was harvested to evaluate lesion size and edema. Brain tissue was processed for RNA sequencing. Gene set enrichment and pathway analysis was performed to determine the differential gene expression patterns following injury.Animals treated with VPA were noted to have a 46% reduction in brain lesion size and a 57% reduction in ipsilateral brain edema. Valproic acid significantly upregulated genes involved in morphology of the nervous system, neuronal development and neuron quantity. The VPA treatment downregulated pathways related to apoptosis, glial cell proliferation, and neuroepithelial cell differentiation. Ingenuity Pathway Analysis identified VPA as the top upstream regulator of activated transcription, supporting it as a direct cause of these transcriptional changes. Master transcriptional regulator NEUROD1 was also significantly upregulated, suggesting that VPA may induce additional transcription factors.Administration of VPA attenuated brain lesion size, reduced brain edema, and induced significant changes in the transcriptome of injured brain within 6 hours. Patterns of differential expression were consistent with the proposed neurogenic and prosurvival effects of VPA treatment.