Valproic acid treatment rescues injured tissues after traumatic brain injury

Ben E. Biesterveld, Luke Pumiglia, Ariella Iancu, Alizeh A. Shamshad, Henriette A. Remmer, Ali Z. Siddiqui, Rachel L. O'Connell, Glenn K. Wakam, Michael T. Kemp, Aaron M. Williams, Manjunath P. Pai, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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 has 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 prosurvival 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 for 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 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 (3,837 ± 948 mm3) compared with the controls (1,900 ± 614 mm3). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 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. CONCLUSION Valproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival 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.

Original languageEnglish (US)
Pages (from-to)1156-1165
Number of pages10
JournalJournal of Trauma and Acute Care Surgery
Issue number6
StatePublished - Dec 2020
Externally publishedYes


  • TBI
  • VPA
  • histone deacetylase
  • swine

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Surgery


Dive into the research topics of 'Valproic acid treatment rescues injured tissues after traumatic brain injury'. Together they form a unique fingerprint.

Cite this