Valproic acid treatment rescues injured tissues after traumatic brain injury

Ben E. Biesterveld; Luke Pumiglia; Ariella Iancu; Alizeh A. Shamshad; Henriette A. Remmer; Ali Z. Siddiqui; Rachel L. O'Connell; Glenn K. Wakam; Michael T. Kemp; Aaron M. Williams; Manjunath P. Pai; Hasan B. Alam

doi:10.1097/TA.0000000000002918

Valproic acid treatment rescues injured tissues after traumatic brain injury

Ben E. Biesterveld, Luke Pumiglia, Ariella Iancu, Alizeh A. Shamshad, Henriette A. Remmer, Ali Z. Siddiqui, Rachel L. O'Connell, Glenn K. Wakam, Michael T. Kemp, Aaron M. Williams, Manjunath P. Pai, Hasan B. Alam^*

^*Corresponding author for this work

Surgery, Trauma and Critical Care Division

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

BACKGROUND No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it has not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate prosurvival pathways. METHODS Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 1 hour; n = 4) or control (saline vehicle; n = 4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers and subjected to proteomic and pathway analysis. RESULTS Brain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm3) compared with the controls (1,900 ± 614 mm3). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism, and biosynthetic machinery. CONCLUSION Valproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies.

Original language	English (US)
Pages (from-to)	1156-1165
Number of pages	10
Journal	Journal of Trauma and Acute Care Surgery
Volume	89
Issue number	6
DOIs	https://doi.org/10.1097/TA.0000000000002918
State	Published - Dec 2020

Funding

For all authors, no conflicts are declared. B.E.B. is supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number F32GM130010. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by the Joyce and Don Massey TBI Foundation.

Keywords

HDACI
TBI
VPA
histone deacetylase
swine

ASJC Scopus subject areas

Surgery
Critical Care and Intensive Care Medicine

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10.1097/TA.0000000000002918

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Biesterveld, B. E., Pumiglia, L., Iancu, A., Shamshad, A. A., Remmer, H. A., Siddiqui, A. Z., O'Connell, R. L., Wakam, G. K., Kemp, M. T., Williams, A. M., Pai, M. P., & Alam, H. B. (2020). Valproic acid treatment rescues injured tissues after traumatic brain injury. Journal of Trauma and Acute Care Surgery, 89(6), 1156-1165. https://doi.org/10.1097/TA.0000000000002918

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title = "Valproic acid treatment rescues injured tissues after traumatic brain injury",

abstract = "BACKGROUND No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it has not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate prosurvival pathways. METHODS Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 1 hour; n = 4) or control (saline vehicle; n = 4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers and subjected to proteomic and pathway analysis. RESULTS Brain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm3) compared with the controls (1,900 ± 614 mm3). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism, and biosynthetic machinery. CONCLUSION Valproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies.",

keywords = "HDACI, TBI, VPA, histone deacetylase, swine",

author = "Biesterveld, {Ben E.} and Luke Pumiglia and Ariella Iancu and Shamshad, {Alizeh A.} and Remmer, {Henriette A.} and Siddiqui, {Ali Z.} and O'Connell, {Rachel L.} and Wakam, {Glenn K.} and Kemp, {Michael T.} and Williams, {Aaron M.} and Pai, {Manjunath P.} and Alam, {Hasan B.}",

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doi = "10.1097/TA.0000000000002918",

language = "English (US)",

volume = "89",

pages = "1156--1165",

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T1 - Valproic acid treatment rescues injured tissues after traumatic brain injury

AU - Biesterveld, Ben E.

AU - Pumiglia, Luke

AU - Iancu, Ariella

AU - Shamshad, Alizeh A.

AU - Remmer, Henriette A.

AU - Siddiqui, Ali Z.

AU - O'Connell, Rachel L.

AU - Wakam, Glenn K.

AU - Kemp, Michael T.

AU - Williams, Aaron M.

AU - Pai, Manjunath P.

AU - Alam, Hasan B.

PY - 2020/12

Y1 - 2020/12

N2 - BACKGROUND No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it has not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate prosurvival pathways. METHODS Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 1 hour; n = 4) or control (saline vehicle; n = 4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers and subjected to proteomic and pathway analysis. RESULTS Brain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm3) compared with the controls (1,900 ± 614 mm3). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism, and biosynthetic machinery. CONCLUSION Valproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies.

AB - BACKGROUND No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it has not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate prosurvival pathways. METHODS Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 1 hour; n = 4) or control (saline vehicle; n = 4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers and subjected to proteomic and pathway analysis. RESULTS Brain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm3) compared with the controls (1,900 ± 614 mm3). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism, and biosynthetic machinery. CONCLUSION Valproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies.

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KW - VPA

KW - histone deacetylase

KW - swine

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Valproic acid treatment rescues injured tissues after traumatic brain injury

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