Isoform 6-selective Histone Deacetylase Inhibition Reduces Lesion Size and Brain Swelling Following Traumatic Brain Injury and Hemorrhagic Shock

Background Non-selective 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 lesser side 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% O2, glucose-free, serum-free medium, 18 hours) and reoxygenation (21% O2, normal culture media, 4 hours) +/- VPA (4mM) or ACY1083 (30nM, 300nM). Cell viability was measured by methylthiazolyl tetrazolium (MTT) assay. Expression of hypoxia-inducible factor-1α (HIF1α), heat shock protein 70 (HSP70), and effectors in the phosphoinositide-3 kinase (PI3K)/mTOR pathway were measured by Western Blot analysis. Additionally, swine were subjected to combined TBI and HS and randomized to three treatment groups (n=5/group): (i) normal saline (NS; 3x hemorrhage volume); (ii) NS + VPA (NS; 3x hemorrhage volume, VPA; 150 mg/kg), and (iii) NS + ACY-1083 (NS; 3x 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 HIF1α expression and upregulated phosphorylated mTOR and HSP70 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 non-selective HDAC inhibition in large animal models of TBI and hemorrhagic shock. Level of evidence not applicable (preclinical study) Address for Correspondence: Hasan B. Alam, MD, Norman Thompson Professor of Surgery, Head of General Surgery, University of Michigan, 2920 Taubman Center/5331, University of Michigan Hospital, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5331, alamh@med.umich.edu, (734) 936-5823 phone, (734) 936-5830 fax Funding: 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. Meeting presentation: Parts of this study were presented at the American College of Surgeons 2016 Clinical Congress. Washington, DC, October 2016. Author Disclosure Statement: No competing financial interests to disclose. © 2018 Lippincott Williams & Wilkins, Inc.

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