Valproic Acid and Neural Apoptosis, Inflammation, and Degeneration 30 Days after Traumatic Brain Injury, Hemorrhagic Shock, and Polytrauma in a Swine Model

Panpan Chang, Aaron M. Williams, Umar F. Bhatti, Ben E. Biesterveld, Baoling Liu, Vahagn C. Nikolian, Isabel S. Dennahy, Jessica Lee, Yongqing Li, Hasan B. Alam

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Background: A single-dose (150 mg/kg) of valproic acid (VPA) has been shown to decrease brain lesion size and improve neurologic recovery in preclinical models of traumatic brain injury (TBI). However, the longer-term (30 days) impact of single-dose VPA treatment after TBI has not been well evaluated. Study Design: Yorkshire swine were subjected to TBI (cortical impact), hemorrhagic shock, and polytrauma. Animals remained in hypovolemic shock for 2 hours before resuscitation with normal saline (NS; volume = 3× hemorrhaged volume) or NS + VPA (150 mg/kg) (n = 5/cohort). Brain samples were harvested 30 days after injuries. The cerebral cortex adjacent to the site of cortical impact was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, and Western blot analysis. Neural apoptosis, inflammation, degeneration, plasticity, and signaling pathways were evaluated. Results: For apoptosis, VPA treatment significantly decreased (p < 0.05) the number of TUNEL (+) cells and expression of cleaved-caspase 3. For inflammation and degeneration, expression of ionized calcium binding adaptor molecule-1, glial fibrillary acid protein, amyloid-β, and phosphorylated-Tau protein were significantly attenuated (p < 0.05) in the VPA-treated animals compared with the NS group. For, plasticity, VPA treatment also increased expression of brain-derived neurotrophic factor significantly (p < 0.05) compared with the NS group. For signaling pathways, nuclear factor-κB was decreased significantly (p < 0.05) and cytosolic IκBα expression was increased significantly (p < 0.05) in the VPA-treated animals compared with the NS group. Conclusions: Administration of a single dose of VPA (150 mg/kg) can decrease neural apoptosis, inflammation, and degenerative changes, and promote neural plasticity at 30 days after TBI. In addition, VPA acts, in part, via regulation of nuclear factor-κB and IκBα pathways.

Original languageEnglish (US)
Pages (from-to)265-275
Number of pages11
JournalJournal of the American College of Surgeons
Volume228
Issue number3
DOIs
StatePublished - Mar 2019
Externally publishedYes

ASJC Scopus subject areas

  • Surgery

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