Isoform 6-selective histone deacetylase inhibition reduces lesion size and brain swelling following traumatic brain injury and hemorrhagic shock

Vahagn C. Nikolian, Isabel S. Dennahy, Michael Weykamp, Aaron M. Williams, Umar F. Bhatti, Hassan Eidy, Mohamed H. Ghandour, Kiril Chtraklin, Yongqing Li, Hasan B. Alam

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

BACKGROUND Nonselective histone deacetylase (pan-HDAC) inhibitors, such as valproic acid (VPA), have demonstrated neuroprotective properties in trauma models. However, isoform-specific HDAC inhibitors may provide opportunity for more effective drug administration with fewer adverse effects. We investigated HDAC6 inhibition with ACY-1083 in an in vitro and an in vivo large animal model of injury. METHODS Mouse hippocampal cells were subjected to oxygen-glucose deprivation (0% O 2, glucose-free and serum-free medium, 18 hours) and reoxygenation (21% O 2, normal culture media, 4 hours) with/without VPA (4 mmol/L) or ACY-1083 (30 nmol/L, 300 nmol/L). Cell viability was measured by methylthiazolyl tetrazolium assay. Expression of hypoxia-inducible factor-1α, heat shock protein 70, and effectors in the phosphoinositide-3 kinase/mammalian target of rapamycin pathway were measured by Western blot analysis. Additionally, swine were subjected to combined traumatic brain injury and hemorrhagic shock and randomized to three treatment groups (n = 5/group): (i) normal saline (NS; 3× hemorrhage volume); (ii) NS + VPA (NS; 3× hemorrhage volume, VPA; 150 mg/kg), and (iii) NS + ACY-1083 (NS; 3× hemorrhage volume, ACY-1083; 30 mg/kg). After 6 hours, brain tissue was harvested to assess lesion size and brain swelling. RESULTS Significant improvement in cell viability was seen with both HDAC inhibitors in the in vitro study. ACY-1083 suppressed hypoxia-inducible factor-1α expression and up-regulated phosphorylated mammalian target of rapamycin and heat shock protein 70 in a dose-dependent manner. Lesion size and brain swelling in animals treated with pharmacologic agents (VPA and ACY-1083) were both smaller than in the NS group. No differences were observed between the VPA and ACY-1083 treatment groups. CONCLUSIONS In conclusion, selective inhibition of HDAC6 is as neuroprotective as nonselective HDAC inhibition in large animal models of traumatic brain injury and hemorrhagic shock.

Original languageEnglish (US)
Pages (from-to)232-239
Number of pages8
JournalJournal of Trauma and Acute Care Surgery
Volume86
Issue number2
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

Keywords

  • hemorrhagic shock
  • histone deacetylase inhibitor
  • Isoform selective
  • neuroprotection
  • traumatic brain injury

ASJC Scopus subject areas

  • Surgery
  • Critical Care and Intensive Care Medicine

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