TY - JOUR
T1 - Isoform 6-selective histone deacetylase inhibition reduces lesion size and brain swelling following traumatic brain injury and hemorrhagic shock
AU - Nikolian, Vahagn C.
AU - Dennahy, Isabel S.
AU - Weykamp, Michael
AU - Williams, Aaron M.
AU - Bhatti, Umar F.
AU - Eidy, Hassan
AU - Ghandour, Mohamed H.
AU - Chtraklin, Kiril
AU - Li, Yongqing
AU - Alam, Hasan B.
N1 - Funding Information:
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.
Publisher Copyright:
© 2018 American Association for the Surgery of Trauma.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
KW - hemorrhagic shock
KW - histone deacetylase inhibitor
KW - Isoform selective
KW - neuroprotection
KW - traumatic brain injury
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U2 - 10.1097/TA.0000000000002119
DO - 10.1097/TA.0000000000002119
M3 - Article
C2 - 30399139
AN - SCOPUS:85060786208
SN - 2163-0755
VL - 86
SP - 232
EP - 239
JO - Journal of Trauma and Acute Care Surgery
JF - Journal of Trauma and Acute Care Surgery
IS - 2
ER -