Molecular Neurobiology

, Volume 52, Issue 3, pp 1119–1134 | Cite as

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury

  • Brandon P. Lucke-Wold
  • Aric F. Logsdon
  • Kelly E. Smith
  • Ryan C. Turner
  • Daniel L. Alkon
  • Zhenjun Tan
  • Zachary J. Naser
  • Chelsea M. Knotts
  • Jason D. Huber
  • Charles L. RosenEmail author


Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the ‘signature injury’ of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague–Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan’s blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan’s blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t = 4.808, p < 0.05), and a reduction back toward control levels when bryostatin-1 was administered (t = 5.113, p < 0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t = 4.559, p < 0.01) and increased the neuroprotective isozyme PKCε (t = 6.102, p < 0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.


Blood brain barrier Bryostatin-1 Protein kinase C Tight junction proteins 





Glial fibrillary acidic protein




Protein kinase C


Single blast

SB + Bryo

Single blast + bryostatin-1


Von Willebrand factor



The authors would like to thank Ryan W. Holt for his help with IHC and western blot analysis. We thank Diana Richardson CDC/NIOSH for tissue preparation for IHC. The authors also thank Dr. Rae Matsumoto and Dr. Steven Frisch for use of western blot resources in their respective laboratories. We thank James E. Robson and Peter Bennett for construction of the blast model and Dr. Robert Gettens and Nic St. John for design of the blast model. A Research Funding and Development Grant (RFDG) from the West Virginia University Health Sciences Center Office of Research and Graduate Education supported this work along with WVU Department of Neurosurgery. R.C.T. was supported by a NIH training grant (GM08174).

Conflicts of Interest

The authors claim to have no conflicts of interest.

Supplementary material

12035_2014_8902_Fig11_ESM.gif (42 kb)
Supplementary Fig. 1

Blast-exposed animals have greater number of cells co-localized with PKCα and VWF. Staining for groups: red = PKCα, green = VWF, and yellow = overlay. Regions analyzed for ratio of positive cells to total cells. Representative section for control group PKCα (a) with inlay (b), VWF (c) with inlay (d), and overlay (e) with inlay (f). Representative section for single blast exposed group PKCα (g) with inlay (h), VWF (i) with inlay (j), and overlay (k) with inlay (l). Representative section for single blast + bryostatin-1 group PKCα (m) with inlay (n), VWF (o) with inlay (p), and overlay (q) with inlay (r) (GIF 41 kb)

12035_2014_8902_MOESM1_ESM.tif (2.2 mb)
High resolution image (TIFF 2227 kb)


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Brandon P. Lucke-Wold
    • 1
    • 2
  • Aric F. Logsdon
    • 2
    • 3
  • Kelly E. Smith
    • 2
    • 3
  • Ryan C. Turner
    • 1
    • 2
  • Daniel L. Alkon
    • 4
  • Zhenjun Tan
    • 1
    • 2
  • Zachary J. Naser
    • 1
    • 2
    • 5
  • Chelsea M. Knotts
    • 1
  • Jason D. Huber
    • 2
    • 3
  • Charles L. Rosen
    • 1
    • 2
    • 6
    Email author
  1. 1.Department of NeurosurgeryWest Virginia University School of MedicineMorgantownUSA
  2. 2.The Center for NeuroscienceWest Virginia University School of MedicineMorgantownUSA
  3. 3.Department of Basic Pharmaceutical SciencesWest Virginia University School of PharmacyMorgantownUSA
  4. 4.Blanchette Rockefeller Neurosciences InstituteMorgantownUSA
  5. 5.Office of Professional Studies in Health SciencesDrexel University College of MedicinePhiladelphiaUSA
  6. 6.Department of NeurosurgeryWest Virginia University School of MedicineMorgantownUSA

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