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 mm) compared with the controls (1,900 ± 614 mm). 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.
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 mm) compared with the controls (1,900 ± 614 mm). 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.
Authors: Boris Zybailov; Amber L Mosley; Mihaela E Sardiu; Michael K Coleman; Laurence Florens; Michael P Washburn Journal: J Proteome Res Date: 2006-09 Impact factor: 4.466
Authors: Nancy Carney; Annette M Totten; Cindy O'Reilly; Jamie S Ullman; Gregory W J Hawryluk; Michael J Bell; Susan L Bratton; Randall Chesnut; Odette A Harris; Niranjan Kissoon; Andres M Rubiano; Lori Shutter; Robert C Tasker; Monica S Vavilala; Jack Wilberger; David W Wright; Jamshid Ghajar Journal: Neurosurgery Date: 2017-01-01 Impact factor: 4.654
Authors: Patrick E Georgoff; Ihab Halaweish; Vahagn C Nikolian; Gerald A Higgins; Tess Bonham; Celia Tafatia; Henriette Remmer; Rajasree Menon; Baoling Liu; Yongqing Li; Hasan B Alam Journal: J Trauma Acute Care Surg Date: 2016-12 Impact factor: 3.313
Authors: Yina Du; Geremy C Clair; Denise Al Alam; Soula Danopoulos; Daniel Schnell; Joseph A Kitzmiller; Ravi S Misra; Soumyaroop Bhattacharya; David Warburton; Thomas J Mariani; Gloria S Pryhuber; Jeffrey A Whitsett; Charles Ansong; Yan Xu Journal: Am J Physiol Lung Cell Mol Physiol Date: 2019-07-03 Impact factor: 5.464
Authors: Aaron M Williams; Isabel S Dennahy; Umar F Bhatti; Ben E Biesterveld; Nathan J Graham; Yongqing Li; Hasan B Alam Journal: Shock Date: 2019-09 Impact factor: 3.454
Authors: Hasan B Alam; Fahad Shuja; Muhammad U Butt; Michael Duggan; Yongqing Li; Nikolaos Zacharias; Eugene Y Fukudome; Baoling Liu; Marc Demoya; George C Velmahos Journal: Surgery Date: 2009-06-25 Impact factor: 3.982
Authors: Cecilie Heerdegen Jepsen; Marc A deMoya; Anders Perner; Martin Sillesen; Sisse R Ostrowski; Hasan B Alam; Pär I Johansson Journal: J Trauma Acute Care Surg Date: 2014-08 Impact factor: 3.313
Authors: Frederick K Korley; Vahagn C Nikolian; Aaron M Williams; Isabel S Dennahy; Michael Weykamp; Hasan B Alam Journal: J Neurotrauma Date: 2018-03-13 Impact factor: 5.269
Authors: Ben E Biesterveld; Ali Z Siddiqui; Rachel L O'Connell; Henriette Remmer; Aaron M Williams; Alizeh Shamshad; William M Smith; Michael T Kemp; Glenn K Wakam; Hasan B Alam Journal: J Surg Res Date: 2021-05-20 Impact factor: 2.417
Authors: Ben E Biesterveld; Rachel O'Connell; Michael T Kemp; Glenn K Wakam; Aaron M Williams; Manjunath P Pai; Hasan B Alam Journal: Trauma Surg Acute Care Open Date: 2021-03-17
Authors: Luke Pumiglia; Aaron M Williams; Michael T Kemp; Glenn K Wakam; Hasan B Alam; Ben E Biesterveld Journal: Trauma Surg Acute Care Open Date: 2021-03-24