Effect of pharmacologic resuscitation on the brain gene expression profiles in a swine model of traumatic brain injury and hemorrhage

Dekker, Simone E.; Bambakidis, Ted; Sillesen, Martin; Liu, Baoling; Johnson, Craig; Jin, Guang; Li, Yongqing; Alam, Hasan B.

doi:10.1097/ta.0000000000000345

Cited by 32 publications

(26 citation statements)

References 30 publications

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“…Public databases and sources used in this analysis are specified in Supplementary Table 1. These included experimental results from a swine model of TBI and hemorrhage (5,9). Other primary data included microarray expression data from postmortem human brain tissue obtained from the Human Brain Atlas of the Allen Brain Science Institute (21) and other sources (22).…”

Section: Methodsmentioning

confidence: 99%

“…VPA has been shown to be neuroprotective in animal models of traumatic brain injury (TBI) (5,6), spinal cord injury (7), and in neurodegenerative disease (8). In a swine model of TBI and hemorrhagic shock (HS) VPA decreases brain lesion size, improves neurologic recovery, and down-regulates genes associated with necrosis, apoptosis, and inflammation (9). The HDAC inhibitor, sodium butyrate, with a mechanism of action like that of VPA, has been shown to activate neurogenesis in rodent brain following ischemic injury (10).…”

Section: Introductionmentioning

confidence: 99%

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Network Reconstruction Reveals that Valproic Acid Activates Neurogenic Transcriptional Programs in Adult Brain Following Traumatic Injury

et al. 2017

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ObjectivesTo determine the mechanism of action of valproic acid (VPA) in the adult central nervous system (CNS) following traumatic brain injury (TBI) and hemorrhagic shock (HS).MethodsData were analyzed from different sources, including experiments in a porcine model, data from postmortem human brain, published studies, public and commercial databases.ResultsThe transcriptional program in the CNS following TBI, HS, and VPA treatment includes activation of regulatory pathways that enhance neurogenesis and suppress gliogenesis. Genes which encode the transcription factors (TFs) that specify neuronal cell fate, including MEF2D, MYT1L, NEUROD1, PAX6 and TBR1, and their target genes, are induced by VPA. VPA represses genes responsible for oligodendrogenesis, maintenance of white matter, T-cell activation, angiogenesis, and endothelial cell proliferation, adhesion and chemotaxis. NEUROD1 has regulatory interactions with 38% of the genes regulated by VPA in a swine model of TBI and HS in adult brain. Hi-C spatial mapping of a VPA pharmacogenomic SNP in the GRIN2B gene shows it is part of a transcriptional hub that contacts 12 genes that mediate chromatin-mediated neurogenesis and neuroplasticity.ConclusionsFollowing TBI and HS, this study shows that VPA administration acts in the adult brain through differential activation of TFs responsible for neurogenesis, genes responsible for neuroplasticity, and repression of TFs that specify oligodendrocyte cell fate, endothelial cell chemotaxis and angiogenesis.Short title: Mechanism of action of valproic acid in traumatic brain injuryElectronic supplementary materialThe online version of this article (doi:10.1007/s11095-017-2130-6) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Network Reconstruction Reveals that Valproic Acid Activates Neurogenic Transcriptional Programs in Adult Brain Following Traumatic Injury

et al. 2017

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“…A growing body of literature suggests that valproic acid may alter gene expression and protein functions following TBI (Dekker, 2014b; Halaweish, 2015b; Bambakidis 2016). Valproic acid has been in clinical use as a mood stabilizing and anti-epileptic and drug since the 1970s.…”

Section: Novel Resuscitation Techniques – Epigenetic Modulation Usingmentioning

confidence: 99%

“…We found that 1,668 probe sets mapping to 370 known genes were differentially expressed between hextend versus hextened+VPA groups. These genes were mapped to, among others, pathways related to cell death, apoptosis, and necrosis (Dekker, 2014b). These findings support our hypothesis that valproic acid alters important genes and pathways that could improve survival.…”

Section: Novel Resuscitation Techniques – Epigenetic Modulation Usingmentioning

confidence: 99%

Different resuscitation strategies and novel pharmacologic treatment with valproic acid in traumatic brain injury

Dekker

Nikolian

Sillesen

et al. 2017

J of Neuroscience Research

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Traumatic brain injury (TBI) is a leading cause of death in young adults, and effective treatment strategies have the potential to save many lives. TBI results in coagulopathy, endothelial dysfunction, inflammation, cell death, and impaired epigenetic homeostasis, ultimately leading to morbidity and/or mortality. Commonly used resuscitation fluids such as crystalloids or colloids have several disadvantages, and might even be harmful when administered in large quantities. There is a need for next-generation treatment strategies (especially in the pre-hospital setting) that minimize cellular damage, improve survival, and enhance neurological recovery. Pharmacologic treatment with histone deacetylase inhibitors, such as valproic acid, have shown promising results in animal studies of TBI, and may therefore be excellent example of next-generation therapies. This review briefly describes traditional resuscitation strategies for TBI combined with hemorrhagic shock, and describes preclinical studies on valproic acid as a new pharmacologic agent in the treatment of TBI. It finally discusses limitations and future directions on the use of histone deacetylase inhibitors for the treatment of TBI.

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“…Gene expression profiles for 1668 probe sets mapping to 370 known genes were found to be differentially modulated by VPA treatment in swine, with an overall attenuation of genes encoding apoptosis, cell death, and necrosis. Pathway analysis showed a significant modulation of cell signaling, dendritic cell response, and complement systems in the VPA treated animals (92). Recent data by other investigators has further clarified the mechanisms that are involved in the HDACI-induced neuroprotection.…”

Section: Mechanisms Underlying Vpa-induced Neuroprotectionmentioning

confidence: 99%

Creating a “Prosurvival Phenotype” Through Histone Deacetylase Inhibition

Halaweish

Nikolian

Georgoff

et al. 2015

Shock

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Traumatic injuries and their sequela represent a major source of mortality in the United States and globally. Initial treatment for shock, traumatic brain injury, and polytrauma is limited to resuscitation fluids to replace lost volume. To date, there are no treatments with inherent pro-survival properties. Our lab has investigated the use of histone deacetylase inhibitors (HDACIs) as pharmacological agents to improve survival. This class of drugs acts through posttranslational protein modifications and is a direct regulator of chromatin structure and function, as well as the function of numerous cytoplasmic proteins. In models of hemorrhagic shock and polytrauma, administration of HDACIs offers a significant survival advantage, even in the absence of fluid resuscitation. Positive results have also been shown in two-hit models of hemorrhage and sepsis and in hemorrhagic shock combined with traumatic brain injury. Accumulating data generated by our group and others continue to support the use of HDACIs for creation of a pro-survival phenotype. With further research and clinical trials, HDACIs have the potential to be an integral tool in treatment of trauma, especially in the pre-hospital phase.

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Effect of pharmacologic resuscitation on the brain gene expression profiles in a swine model of traumatic brain injury and hemorrhage

Abstract: This is the first high-throughput analysis of cerebral gene profiling following TBI + HS. It shows that treatment with VPA significantly alters early transcription of pathways related to cell survival, which may explain its neuroprotective effects.

Cited by 32 publications

References 30 publications

Network Reconstruction Reveals that Valproic Acid Activates Neurogenic Transcriptional Programs in Adult Brain Following Traumatic Injury

Network Reconstruction Reveals that Valproic Acid Activates Neurogenic Transcriptional Programs in Adult Brain Following Traumatic Injury

Different resuscitation strategies and novel pharmacologic treatment with valproic acid in traumatic brain injury

Creating a “Prosurvival Phenotype” Through Histone Deacetylase Inhibition

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