A single dose of valproic acid improves neurologic recovery and decreases brain lesion size in swine subjected to an isolated traumatic brain injury

Glenn K. Wakam; Ben E. Biesterveld; Manjunath P. Pai; Michael T. Kemp; Rachel L. O'Connell; Krishani K. Rajanayake; Kiril Chtraklin; Claire A. Vercruysse; Hasan B. Alam

doi:10.1097/TA.0000000000003136

A single dose of valproic acid improves neurologic recovery and decreases brain lesion size in swine subjected to an isolated traumatic brain injury

Glenn K. Wakam, Ben E. Biesterveld, Manjunath P. Pai, Michael T. Kemp, Rachel L. O'Connell, Krishani K. Rajanayake, Kiril Chtraklin, Claire A. Vercruysse, Hasan B. Alam^*

^*Corresponding author for this work

Surgery, Trauma and Critical Care Division

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

6 Scopus citations

Abstract

BACKGROUND: We lack specific treatments for traumatic brain injury (TBI), which remains the leading cause of trauma-related morbidity and mortality. Treatment with valproic acid (VPA) improves outcomes in models of severe TBI with concurrent hemorrhage. However, it is unknown if VPA will have similar benefits after isolated nonlethal TBI, which is the more common clinical scenario. The goal of this study was to evaluate the effect of VPA treatment in a preclinical isolated TBI swine model on neurologic outcomes and brain lesion size and to perform detailed pharmacokinetic analyses for a future clinical trial. METHODS: Yorkshire swine (n = 10; 5/cohort) were subjected to TBI (8-mm controlled cortical impact). An hour later, we randomized them to receive VPA (150 mg/kg) or saline placebo (control). Neuroseverity scores were assessed daily (0 [normal] to 36 [comatose]), brain lesion size was measured on postinjury 3, and serial blood samples were collected for pharmacokinetic studies. RESULTS: Physiologic parameters and laboratory values were similar in both groups. Valproic acid–treated animals demonstrated significantly better neuroseverity scores on postinjury 1 (control, 9.2 ± 4.4; VPA, 0 ± 0; p = 0.001). Valproic acid–treated animals had significantly smaller brain lesion sizes (mean volume in microliter: control, 3,130 ± 2,166; VPA, 764 ± 208; p = 0.02). Pharmacokinetic data confirmed adequate plasma and tissue levels of VPA. CONCLUSION: In this clinically relevant model of isolated TBI, a single dose of VPA attenuates neurological impairment and decreases brain lesion size.

Original language	English (US)
Pages (from-to)	867-871
Number of pages	5
Journal	Journal of Trauma and Acute Care Surgery
Volume	91
Issue number	5
DOIs	https://doi.org/10.1097/TA.0000000000003136
State	Published - Nov 2021

Funding

The authors declare no conflicts of interest. This work was supported by the US Army Medical Research and Materiel Command under contract number W81XWH-17-C-0246 to H.B.A. In addition, B.E.B. was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number F32GM130010. The views, opinions, and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy, or decision unless so designated by other documentation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords

Neuroprotection
preclinical swine model
swine
traumatic brain injury
valproic acid

ASJC Scopus subject areas

Critical Care and Intensive Care Medicine
Surgery

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Wakam, G. K., Biesterveld, B. E., Pai, M. P., Kemp, M. T., O'Connell, R. L., Rajanayake, K. K., Chtraklin, K., Vercruysse, C. A., & Alam, H. B. (2021). A single dose of valproic acid improves neurologic recovery and decreases brain lesion size in swine subjected to an isolated traumatic brain injury. Journal of Trauma and Acute Care Surgery, 91(5), 867-871. https://doi.org/10.1097/TA.0000000000003136

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title = "A single dose of valproic acid improves neurologic recovery and decreases brain lesion size in swine subjected to an isolated traumatic brain injury",

abstract = "BACKGROUND: We lack specific treatments for traumatic brain injury (TBI), which remains the leading cause of trauma-related morbidity and mortality. Treatment with valproic acid (VPA) improves outcomes in models of severe TBI with concurrent hemorrhage. However, it is unknown if VPA will have similar benefits after isolated nonlethal TBI, which is the more common clinical scenario. The goal of this study was to evaluate the effect of VPA treatment in a preclinical isolated TBI swine model on neurologic outcomes and brain lesion size and to perform detailed pharmacokinetic analyses for a future clinical trial. METHODS: Yorkshire swine (n = 10; 5/cohort) were subjected to TBI (8-mm controlled cortical impact). An hour later, we randomized them to receive VPA (150 mg/kg) or saline placebo (control). Neuroseverity scores were assessed daily (0 [normal] to 36 [comatose]), brain lesion size was measured on postinjury 3, and serial blood samples were collected for pharmacokinetic studies. RESULTS: Physiologic parameters and laboratory values were similar in both groups. Valproic acid–treated animals demonstrated significantly better neuroseverity scores on postinjury 1 (control, 9.2 ± 4.4; VPA, 0 ± 0; p = 0.001). Valproic acid–treated animals had significantly smaller brain lesion sizes (mean volume in microliter: control, 3,130 ± 2,166; VPA, 764 ± 208; p = 0.02). Pharmacokinetic data confirmed adequate plasma and tissue levels of VPA. CONCLUSION: In this clinically relevant model of isolated TBI, a single dose of VPA attenuates neurological impairment and decreases brain lesion size.",

keywords = "Neuroprotection, preclinical swine model, swine, traumatic brain injury, valproic acid",

author = "Wakam, {Glenn K.} and Biesterveld, {Ben E.} and Pai, {Manjunath P.} and Kemp, {Michael T.} and O'Connell, {Rachel L.} and Rajanayake, {Krishani K.} and Kiril Chtraklin and Vercruysse, {Claire A.} and Alam, {Hasan B.}",

year = "2021",

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doi = "10.1097/TA.0000000000003136",

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volume = "91",

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Wakam, GK, Biesterveld, BE, Pai, MP, Kemp, MT, O'Connell, RL, Rajanayake, KK, Chtraklin, K, Vercruysse, CA & Alam, HB 2021, 'A single dose of valproic acid improves neurologic recovery and decreases brain lesion size in swine subjected to an isolated traumatic brain injury', Journal of Trauma and Acute Care Surgery, vol. 91, no. 5, pp. 867-871. https://doi.org/10.1097/TA.0000000000003136

TY - JOUR

T1 - A single dose of valproic acid improves neurologic recovery and decreases brain lesion size in swine subjected to an isolated traumatic brain injury

AU - Wakam, Glenn K.

AU - Biesterveld, Ben E.

AU - Pai, Manjunath P.

AU - Kemp, Michael T.

AU - O'Connell, Rachel L.

AU - Rajanayake, Krishani K.

AU - Chtraklin, Kiril

AU - Vercruysse, Claire A.

AU - Alam, Hasan B.

PY - 2021/11

Y1 - 2021/11

N2 - BACKGROUND: We lack specific treatments for traumatic brain injury (TBI), which remains the leading cause of trauma-related morbidity and mortality. Treatment with valproic acid (VPA) improves outcomes in models of severe TBI with concurrent hemorrhage. However, it is unknown if VPA will have similar benefits after isolated nonlethal TBI, which is the more common clinical scenario. The goal of this study was to evaluate the effect of VPA treatment in a preclinical isolated TBI swine model on neurologic outcomes and brain lesion size and to perform detailed pharmacokinetic analyses for a future clinical trial. METHODS: Yorkshire swine (n = 10; 5/cohort) were subjected to TBI (8-mm controlled cortical impact). An hour later, we randomized them to receive VPA (150 mg/kg) or saline placebo (control). Neuroseverity scores were assessed daily (0 [normal] to 36 [comatose]), brain lesion size was measured on postinjury 3, and serial blood samples were collected for pharmacokinetic studies. RESULTS: Physiologic parameters and laboratory values were similar in both groups. Valproic acid–treated animals demonstrated significantly better neuroseverity scores on postinjury 1 (control, 9.2 ± 4.4; VPA, 0 ± 0; p = 0.001). Valproic acid–treated animals had significantly smaller brain lesion sizes (mean volume in microliter: control, 3,130 ± 2,166; VPA, 764 ± 208; p = 0.02). Pharmacokinetic data confirmed adequate plasma and tissue levels of VPA. CONCLUSION: In this clinically relevant model of isolated TBI, a single dose of VPA attenuates neurological impairment and decreases brain lesion size.

AB - BACKGROUND: We lack specific treatments for traumatic brain injury (TBI), which remains the leading cause of trauma-related morbidity and mortality. Treatment with valproic acid (VPA) improves outcomes in models of severe TBI with concurrent hemorrhage. However, it is unknown if VPA will have similar benefits after isolated nonlethal TBI, which is the more common clinical scenario. The goal of this study was to evaluate the effect of VPA treatment in a preclinical isolated TBI swine model on neurologic outcomes and brain lesion size and to perform detailed pharmacokinetic analyses for a future clinical trial. METHODS: Yorkshire swine (n = 10; 5/cohort) were subjected to TBI (8-mm controlled cortical impact). An hour later, we randomized them to receive VPA (150 mg/kg) or saline placebo (control). Neuroseverity scores were assessed daily (0 [normal] to 36 [comatose]), brain lesion size was measured on postinjury 3, and serial blood samples were collected for pharmacokinetic studies. RESULTS: Physiologic parameters and laboratory values were similar in both groups. Valproic acid–treated animals demonstrated significantly better neuroseverity scores on postinjury 1 (control, 9.2 ± 4.4; VPA, 0 ± 0; p = 0.001). Valproic acid–treated animals had significantly smaller brain lesion sizes (mean volume in microliter: control, 3,130 ± 2,166; VPA, 764 ± 208; p = 0.02). Pharmacokinetic data confirmed adequate plasma and tissue levels of VPA. CONCLUSION: In this clinically relevant model of isolated TBI, a single dose of VPA attenuates neurological impairment and decreases brain lesion size.

KW - Neuroprotection

KW - preclinical swine model

KW - swine

KW - traumatic brain injury

KW - valproic acid

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JO - Journal of Trauma and Acute Care Surgery

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A single dose of valproic acid improves neurologic recovery and decreases brain lesion size in swine subjected to an isolated traumatic brain injury

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