Transcriptomic Changes Following Valproic Acid Treatment Promote Neurogenesis and Minimize Secondary Brain Injury

ABSTRACTBackgroundEarly treatment with valproic acid (VPA) has demonstrated benefit in pre-clinical models of traumatic brain injury (TBI), 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.MethodsTen female swine were subjected to a protocol of TBI and hemorrhagic shock. They were assigned to two groups (n=5): normal saline (NS; 3X 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.ResultsAnimals treated with VPA were noted to have a 46% reduction in brain lesion size and a 57% reduction in ipsilateral brain edema. VPA significantly up-regulated genes involved in morphology of the nervous system, neuronal development and neuron quantity. 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.ConclusionsAdministration 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 pro-survival effects of VPA treatment.Level of evidence: not applicable (pre-clinical study.)Study type: therapeutic. Background Early treatment with valproic acid (VPA) has demonstrated benefit in pre-clinical models of traumatic brain injury (TBI), 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. Methods Ten female swine were subjected to a protocol of TBI and hemorrhagic shock. They were assigned to two groups (n=5): normal saline (NS; 3X 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. Results Animals treated with VPA were noted to have a 46% reduction in brain lesion size and a 57% reduction in ipsilateral brain edema. VPA significantly up-regulated genes involved in morphology of the nervous system, neuronal development and neuron quantity. 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. Conclusions 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 pro-survival effects of VPA treatment. Level of evidence: not applicable (pre-clinical study.) Study type: therapeutic. * Equal contributions, co-first authors. Address for correspondence: Hasan B. Alam, MD, Norman Thompson Professor of Surgery, and Chief of General Surgery, University of Michigan Hospital, 2920 Taubman Center/5331, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5331. alamh@med.umich.edu Conflict of Interest: none to report. Meeting presentation: this study was presented at the 76th Annual Meeting of AAST and Clinical Congress of Acute Care Surgery (Baltimore, MD, September, 2017.) Funding: US Army Medical Research Materiel Command W81XWH-09-1-0520 (Alam, HB); Frederick A. Coller Society Research Fellowship Grant (Nikolian, VC). © 2017 Lippincott Williams & Wilkins, Inc.

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