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 language | English (US) |
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Pages (from-to) | 232-239 |
Number of pages | 8 |
Journal | Journal of Trauma and Acute Care Surgery |
Volume | 86 |
Issue number | 2 |
DOIs | |
State | Published - Feb 1 2019 |
Funding
The authors declare no conflicts of interest. HBA secured funding grant for the study. This work was supported by the US Army Materiel and Research Command, Contract W81XWH-09-1-0520, NIH grant 2 R01 GM084127, and funding from the Massey Foundation Severe TBI Grand Challenge Initiative.
Keywords
- Isoform selective
- hemorrhagic shock
- histone deacetylase inhibitor
- neuroprotection
- traumatic brain injury
ASJC Scopus subject areas
- Surgery
- Critical Care and Intensive Care Medicine