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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
Article

Abstract

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.

Keywords

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

Abbreviations

CTRL

Control

GFAP

Glial fibrillary acidic protein

IHC

Immunohistochemistry

PKC

Protein kinase C

SB

Single blast

SB + Bryo

Single blast + bryostatin-1

VWF

Von Willebrand factor

Notes

Acknowledgments

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)

References

  1. 1.
    Kou Z, Vandevord PJ (2014) Traumatic white matter injury and glial activation: from basic science to clinics. Glia. doi: 10.1002/glia.22690 PubMedGoogle Scholar
  2. 2.
    Schneider EB, Sur S, Raymont V, Duckworth J, Kowalski RG, Efron DT, Hui X, Selvarajah S, Hambridge HL, Stevens RD (2014) Functional recovery after moderate/severe traumatic brain injury: a role for cognitive reserve? Neurology 82(18):1636–1642. doi: 10.1212/WNL.0000000000000379 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Puvenna V, Brennan C, Shaw G, Yang C, Marchi N, Bazarian JJ, Merchant-Borna K, Janigro D (2014) Significance of ubiquitin carboxy-terminal hydrolase l1 elevations in athletes after sub-concussive head hits. PLoS One 9(5):e96296. doi: 10.1371/journal.pone.0096296 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Simard JMMDPD, Pampori A, Keledjian K, Tosun C, Schwartzbauer G, Ivanova S, Gerzanich V (2014) Exposure of the thorax to a sublethal blast wave causes a hydrodynamic pulse that leads to perivenular inflammation in the brain. J Neurotrauma. doi: 10.1089/neu.2013.3016 PubMedPubMedCentralGoogle Scholar
  5. 5.
    Hue CD, Cao S, Dale Bass CR, Meaney DF, Morrison B 3rd (2014) Repeated primary blast injury causes delayed recovery, but not additive disruption, in an in vitro blood–brain barrier model. J Neurotrauma 31(10):951–960. doi: 10.1089/neu.2013.3149 CrossRefPubMedGoogle Scholar
  6. 6.
    Yeoh S, Bell ED, Monson KL (2013) Distribution of blood–brain barrier disruption in primary blast injury. Ann Biomed Eng 41(10):2206–2214. doi: 10.1007/s10439-013-0805-7 CrossRefPubMedGoogle Scholar
  7. 7.
    Abdul-Muneer PM, Schuetz H, Wang F, Skotak M, Jones J, Gorantla S, Zimmerman MC, Chandra N, Haorah J (2013) Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast. Free Radic Biol Med 60:282–291. doi: 10.1016/j.freeradbiomed.2013.02.029 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Perez-Polo JR, Rea HC, Johnson KM, Parsley MA, Unabia GC, Xu G, Infante SK, Dewitt DS, Hulsebosch CE (2013) Inflammatory consequences in a rodent model of mild traumatic brain injury. J Neurotrauma 30(9):727–740. doi: 10.1089/neu.2012.2650 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Readnower RD, Chavko M, Adeeb S, Conroy MD, Pauly JR, McCarron RM, Sullivan PG (2010) Increase in blood–brain barrier permeability, oxidative stress, and activated microglia in a rat model of blast-induced traumatic brain injury. J Neurosci Res 88(16):3530–3539. doi: 10.1002/jnr.22510 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Yang K, Taft WC, Dixon CE, Todaro CA, Yu RK, Hayes RL (1993) Alterations of protein kinase C in rat hippocampus following traumatic brain injury. J Neurotrauma 10(3):287–295CrossRefPubMedGoogle Scholar
  11. 11.
    Padmaperuma B, Mark R, Dhillon HS, Mattson MP, Prasad MR (1996) Alterations in brain protein kinase C after experimental brain injury. Brain Res 714(1–2):19–26CrossRefPubMedGoogle Scholar
  12. 12.
    Muscella A, Marsigliante S, Verri T, Urso L, Dimitri C, Botta G, Paulmichl M, Beck-Peccoz P, Fugazzola L, Storelli C (2008) PKC-epsilon-dependent cytosol-to-membrane translocation of pendrin in rat thyroid PC Cl3 cells. J Cell Physiol 217(1):103–112. doi: 10.1002/jcp.21478 CrossRefPubMedGoogle Scholar
  13. 13.
    Chen T, Cao L, Dong W, Luo P, Liu W, Qu Y, Fei Z (2012) Protective effects of mGluR5 positive modulators against traumatic neuronal injury through PKC-dependent activation of MEK/ERK pathway. Neurochem Res 37(5):983–990. doi: 10.1007/s11064-011-0691-z CrossRefPubMedGoogle Scholar
  14. 14.
    Luo P, Chen T, Zhao Y, Zhang L, Yang Y, Liu W, Li S, Rao W, Dai S, Yang J, Fei Z (2014) Postsynaptic scaffold protein Homer 1a protects against traumatic brain injury via regulating group I metabotropic glutamate receptors. Cell Death Dis 5:e1174. doi: 10.1038/cddis.2014.116 CrossRefPubMedGoogle Scholar
  15. 15.
    Geddes-Klein DM, Serbest G, Mesfin MN, Cohen AS, Meaney DF (2006) Pharmacologically induced calcium oscillations protect neurons from increases in cytosolic calcium after trauma. J Neurochem 97(2):462–474. doi: 10.1111/j.1471-4159.2006.03761.x CrossRefPubMedGoogle Scholar
  16. 16.
    Roh DH, Yoon SY, Seo HS, Kang SY, Moon JY, Song S, Beitz AJ, Lee JH (2010) Sigma-1 receptor-induced increase in murine spinal NR1 phosphorylation is mediated by the PKCalpha and epsilon, but not the PKCzeta, isoforms. Neurosci Lett 477(2):95–99. doi: 10.1016/j.neulet.2010.04.041 CrossRefPubMedGoogle Scholar
  17. 17.
    Giordano G, Sanchez-Perez AM, Burgal M, Montoliu C, Costa LG, Felipo V (2005) Chronic exposure to ammonia induces isoform-selective alterations in the intracellular distribution and NMDA receptor-mediated translocation of protein kinase C in cerebellar neurons in culture. J Neurochem 92(1):143–157. doi: 10.1111/j.1471-4159.2004.02852.x CrossRefPubMedGoogle Scholar
  18. 18.
    Pandya JD, Nukala VN, Sullivan PG (2013) Concentration dependent effect of calcium on brain mitochondrial bioenergetics and oxidative stress parameters. Front Neuroenerg 5:10. doi: 10.3389/fnene.2013.00010 CrossRefGoogle Scholar
  19. 19.
    Yang K, Taft WC, Dixon CE, Yu RK, Hayes RL (1994) Endogenous phosphorylation of a 61,000 dalton hippocampal protein increases following traumatic brain injury. J Neurotrauma 11(5):523–532CrossRefPubMedGoogle Scholar
  20. 20.
    Karasu A, Aras Y, Sabanci PA, Saglam G, Izgi N, Biltekin B, Barak T, Hepgul KT, Kaya M, Bilir A (2010) The effects of protein kinase C activator phorbol dibutyrate on traumatic brain edema and aquaporin-4 expression. Ulusal travma ve acil cerrahi dergisi. Turk J Trauma Emerg Surg TJTES 16(5):390–394Google Scholar
  21. 21.
    Kim YA, Park SL, Kim MY, Lee SH, Baik EJ, Moon CH, Jung YS (2010) Role of PKCbetaII and PKCdelta in blood–brain barrier permeability during aglycemic hypoxia. Neurosci Lett 468(3):254–258. doi: 10.1016/j.neulet.2009.11.007 CrossRefPubMedGoogle Scholar
  22. 22.
    Kizub IV, Klymenko KI, Soloviev AI (2014) Protein kinase C in enhanced vascular tone in diabetes mellitus. Int J Cardiol 174(2):230–242. doi: 10.1016/j.ijcard.2014.04.117 CrossRefPubMedGoogle Scholar
  23. 23.
    Lin HW, Della-Morte D, Thompson JW, Gresia VL, Narayanan SV, Defazio RA, Raval AP, Saul I, Dave KR, Morris KC, Si ML, Perez-Pinzon MA (2012) Differential effects of delta and epsilon protein kinase C in modulation of postischemic cerebral blood flow. Adv Exp Med Biol 737:63–69. doi: 10.1007/978-1-4614-1566-4_10 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zohar O, Lavy R, Zi X, Nelson TJ, Hongpaisan J, Pick CG, Alkon DL (2011) PKC activator therapeutic for mild traumatic brain injury in mice. Neurobiol Dis 41(2):329–337. doi: 10.1016/j.nbd.2010.10.001 CrossRefPubMedGoogle Scholar
  25. 25.
    Lim CS, Alkon DL (2014) PKCepsilon promotes HuD-mediated neprilysin mRNA stability and enhances neprilysin-induced Abeta degradation in brain neurons. PLoS One 9(5):e97756. doi: 10.1371/journal.pone.0097756 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Xu C, Liu QY, Alkon DL (2014) PKC activators enhance GABAergic neurotransmission and paired-pulse facilitation in hippocampal CA1 pyramidal neurons. Neuroscience 268:75–86. doi: 10.1016/j.neuroscience.2014.03.008 CrossRefPubMedGoogle Scholar
  27. 27.
    Hongpaisan J, Sun MK, Alkon DL (2011) PKC epsilon activation prevents synaptic loss, Abeta elevation, and cognitive deficits in Alzheimer's disease transgenic mice. J Neurosci Off J Soc Neurosci 31(2):630–643. doi: 10.1523/JNEUROSCI.5209-10.2011 CrossRefGoogle Scholar
  28. 28.
    Tan Z, Turner RC, Leon RL, Li X, Hongpaisan J, Zheng W, Logsdon AF, Naser ZJ, Alkon DL, Rosen CL, Huber JD (2013) Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke. Stroke J Cereb Circ 44(12):3490–3497. doi: 10.1161/STROKEAHA.113.002411 CrossRefGoogle Scholar
  29. 29.
    Turner RC, Naser ZJ, Logsdon AF, DiPasquale KH, Jackson GJ, Robson MJ, Gettens RT, Matsumoto RR, Huber JD, Rosen CL (2013) Modeling clinically relevant blast parameters based on scaling principles produces functional histological deficits in rats. Exp Neurol 248:520–529. doi: 10.1016/j.expneurol.2013.07.008 CrossRefPubMedGoogle Scholar
  30. 30.
    Morrow CM, Mruk D, Cheng CY, Hess RA (2010) Claudin and occludin expression and function in the seminiferous epithelium. Philos Trans R Soc Lond B Biol Sci 365(1546):1679–1696. doi: 10.1098/rstb.2010.0025 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Goncalves A, Leal E, Paiva A, Teixeira Lemos E, Teixeira F, Ribeiro CF, Reis F, Ambrosio AF, Fernandes R (2012) Protective effects of the dipeptidyl peptidase IV inhibitor sitagliptin in the blood-retinal barrier in a type 2 diabetes animal model. Diabetes Obes Metab 14(5):454–463. doi: 10.1111/j.1463-1326.2011.01548.x CrossRefPubMedGoogle Scholar
  32. 32.
    Sun MK, Alkon DL (2006) Bryostatin-1: pharmacology and therapeutic potential as a CNS drug. CNS Drug Rev 12(1):1–8. doi: 10.1111/j.1527-3458.2006.00001.x CrossRefPubMedGoogle Scholar
  33. 33.
    Berkow RL, Schlabach L, Dodson R, Benjamin WH Jr, Pettit GR, Rustagi P, Kraft AS (1993) In vivo administration of the anticancer agent bryostatin 1 activates platelets and neutrophils and modulates protein kinase C activity. Cancer Res 53(12):2810–2815PubMedGoogle Scholar
  34. 34.
    Sun MK, Hongpaisan J, Lim CS, Alkon DL (2014) Bryostatin-1 restores hippocampal synapses and spatial learning and memory in adult fragile x mice. J Pharmacol Exp Ther 349(3):393–401. doi: 10.1124/jpet.114.214098 CrossRefPubMedGoogle Scholar
  35. 35.
    Turner RC, Naser ZJ, Bailes JE, Smith DW, Fisher JA, Rosen CL (2012) Effect of slosh mitigation on histologic markers of traumatic brain injury: laboratory investigation. J Neurosurg 117(6):1110–1118. doi: 10.3171/2012.8.JNS12358 CrossRefPubMedGoogle Scholar
  36. 36.
    Bass CR, Panzer MB, Rafaels KA, Wood G, Shridharani J, Capehart B (2012) Brain injuries from blast. Ann Biomed Eng 40(1):185–202. doi: 10.1007/s10439-011-0424-0 CrossRefPubMedGoogle Scholar
  37. 37.
    Panzer MB, Wood GW, Bass CR (2014) Scaling in neurotrauma: how do we apply animal experiments to people? Exp Neurol. doi: 10.1016/j.expneurol.2014.07.002 PubMedGoogle Scholar
  38. 38.
    Yen LF, Wei VC, Kuo EY, Lai TW (2013) Distinct patterns of cerebral extravasation by Evans blue and sodium fluorescein in rats. PLoS One 8(7):e68595. doi: 10.1371/journal.pone.0068595 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Dinapoli VA, Benkovic SA, Li X, Kelly KA, Miller DB, Rosen CL, Huber JD, O'Callaghan JP (2010) Age exaggerates proinflammatory cytokine signaling and truncates signal transducers and activators of transcription 3 signaling following ischemic stroke in the rat. Neuroscience 170(2):633–644. doi: 10.1016/j.neuroscience.2010.07.011 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Bolte S, Cordelieres FP (2006) A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 224(Pt 3):213–232. doi: 10.1111/j.1365-2818.2006.01706.x CrossRefPubMedGoogle Scholar
  41. 41.
    Girolamo F, Dallatomasina A, Rizzi M, Errede M, Walchli T, Mucignat MT, Frei K, Roncali L, Perris R, Virgintino D (2013) Diversified expression of NG2/CSPG4 isoforms in glioblastoma and human foetal brain identifies pericyte subsets. PLoS One 8(12):e84883. doi: 10.1371/journal.pone.0084883 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Abdul-Muneer PM, Chandra N, Haorah J (2014) Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury. Mol Neurobiol. doi: 10.1007/s12035-014-8752-3 PubMedGoogle Scholar
  43. 43.
    Shao B, Bayraktutan U (2014) Hyperglycaemia promotes human brain microvascular endothelial cell apoptosis via induction of protein kinase C-ssI and prooxidant enzyme NADPH oxidase. Redox Biol 2:694–701. doi: 10.1016/j.redox.2014.05.005 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV (2006) Protein kinase Calpha-RhoA cross-talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem 281(13):8379–8388. doi: 10.1074/jbc.M513122200 CrossRefPubMedGoogle Scholar
  45. 45.
    Xia YP, He QW, Li YN, Chen SC, Huang M, Wang Y, Gao Y, Huang Y, Wang MD, Mao L, Hu B (2013) Recombinant human sonic hedgehog protein regulates the expression of ZO-1 and occludin by activating angiopoietin-1 in stroke damage. PLoS One 8(7):e68891. doi: 10.1371/journal.pone.0068891 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Guo D, Standley C, Bellve K, Fogarty K, Bao ZZ (2012) Protein kinase Calpha and integrin-linked kinase mediate the negative axon guidance effects of Sonic hedgehog. Mol Cell Neurosci 50(1):82–92. doi: 10.1016/j.mcn.2012.03.008 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Chamorro D, Alarcon L, Ponce A, Tapia R, Gonzalez-Aguilar H, Robles-Flores M, Mejia-Castillo T, Segovia J, Bandala Y, Juaristi E, Gonzalez-Mariscal L (2009) Phosphorylation of zona occludens-2 by protein kinase C epsilon regulates its nuclear exportation. Mol Biol Cell 20(18):4120–4129. doi: 10.1091/mbc.E08-11-1129 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Amtul Z, Hepburn JD (2014) Protein markers of cerebrovascular disruption of neurovascular unit: immunohistochemical and imaging approaches. Rev Neurosci. doi: 10.1515/revneuro-2013-0041 PubMedGoogle Scholar
  49. 49.
    Muoio V, Persson PB, Sendeski MM (2014) The neurovascular unit - concept review. Acta Physiol 210(4):790–798. doi: 10.1111/apha.12250 CrossRefGoogle Scholar
  50. 50.
    Sun MK, Hongpaisan J, Alkon DL (2009) Postischemic PKC activation rescues retrograde and anterograde long-term memory. Proc Natl Acad Sci U S A 106(34):14676–14680. doi: 10.1073/pnas.0907842106 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Sun MK, Alkon DL (2014) The "Memory Kinases": roles of PKC isoforms in signal processing and memory formation. Prog Mol Biol Transl Sci 122:31–59. doi: 10.1016/B978-0-12-420170-5.00002-7 CrossRefPubMedGoogle Scholar
  52. 52.
    Lallemend F, Hadjab S, Hans G, Moonen G, Lefebvre PP, Malgrange B (2005) Activation of protein kinase CbetaI constitutes a new neurotrophic pathway for deafferented spiral ganglion neurons. J Cell Sci 118(Pt 19):4511–4525. doi: 10.1242/jcs.02572 CrossRefPubMedGoogle Scholar
  53. 53.
    Wu J, Zhao Z, Sabirzhanov B, Stoica BA, Kumar A, Luo T, Skovira J, Faden AI (2014) Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways. J Neurosci Off J Soc Neurosci 34(33):10989–11006. doi: 10.1523/JNEUROSCI.5110-13.2014 CrossRefGoogle Scholar
  54. 54.
    Lucke-Wold BP, Turner RC, Logsdon AF, Simpkins JW, Alkon DL, Smith KE, Chen YW, Tan Z, Huber JD, Rosen CL (2014) Common mechanisms of Alzheimer's disease and ischemic stroke: the role of protein kinase C in the progression of age-related neurodegeneration. J Alzheimers Dis JAD. doi: 10.3233/JAD-141422 Google Scholar
  55. 55.
    Hoozemans JJ, Scheper W (2012) Endoplasmic reticulum: the unfolded protein response is tangled in neurodegeneration. Int J Biochem Cell Biol 44(8):1295–1298. doi: 10.1016/j.biocel.2012.04.023 CrossRefPubMedGoogle Scholar
  56. 56.
    Sun MK, Hongpaisan J, Nelson TJ, Alkon DL (2008) Poststroke neuronal rescue and synaptogenesis mediated in vivo by protein kinase C in adult brains. Proc Natl Acad Sci U S A 105(36):13620–13625. doi: 10.1073/pnas.0805952105 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Sun MK, Alkon DL (2013) Cerebral ischemia-induced difference in sensitivity to depression and potential therapeutics in rats. Behav Pharmacol 24(3):222–228. doi: 10.1097/FBP.0b013e3283618afe CrossRefPubMedGoogle Scholar
  58. 58.
    Kim H, Han SH, Quan HY, Jung YJ, An J, Kang P, Park JB, Yoon BJ, Seol GH, Min SS (2012) Bryostatin-1 promotes long-term potentiation via activation of PKCalpha and PKCepsilon in the hippocampus. Neuroscience 226:348–355. doi: 10.1016/j.neuroscience.2012.08.055 CrossRefPubMedGoogle Scholar
  59. 59.
    Nelson TJ, Alkon DL (2009) Neuroprotective versus tumorigenic protein kinase C activators. Trends Biochem Sci 34(3):136–145. doi: 10.1016/j.tibs.2008.11.006 CrossRefPubMedGoogle Scholar
  60. 60.
    Mogha A, Guariglia SR, Debata PR, Wen GY, Banerjee P (2012) Serotonin 1A receptor-mediated signaling through ERK and PKCalpha is essential for normal synaptogenesis in neonatal mouse hippocampus. Transl Psychiatry 2:e66. doi: 10.1038/tp.2011.58 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Yu H, Wang P, An P, Xue Y (2012) Recombinant human angiopoietin-1 ameliorates the expressions of ZO-1, occludin, VE-cadherin, and PKCalpha signaling after focal cerebral ischemia/reperfusion in rats. J Mol Neurosci MN 46(1):236–247. doi: 10.1007/s12031-011-9584-5 CrossRefPubMedGoogle Scholar
  62. 62.
    Chodobski A, Zink BJ, Szmydynger-Chodobska J (2011) Blood–brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res 2(4):492–516. doi: 10.1007/s12975-011-0125-x CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Dai SS, Zhou YG, Li W, An JH, Li P, Yang N, Chen XY, Xiong RP, Liu P, Zhao Y, Shen HY, Zhu PF, Chen JF (2010) Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J Neurosci Off J Soc Neurosci 30(16):5802–5810. doi: 10.1523/JNEUROSCI.0268-10.2010 CrossRefGoogle Scholar
  64. 64.
    Novokhatska T, Tishkin S, Dosenko V, Boldyriev A, Ivanova I, Strielkov I, Soloviev A (2013) Correction of vascular hypercontractility in spontaneously hypertensive rats using shRNAs-induced delta protein kinase C gene silencing. Eur J Pharmacol 718(1–3):401–407. doi: 10.1016/j.ejphar.2013.08.003 CrossRefPubMedGoogle Scholar
  65. 65.
    Feng S, Li D, Li Y, Yang X, Han S, Li J (2013) Insight into hypoxic preconditioning and ischemic injury through determination of nPKCepsilon-interacting proteins in mouse brain. Neurochem Int 63(2):69–79. doi: 10.1016/j.neuint.2013.04.011 CrossRefPubMedGoogle Scholar
  66. 66.
    Yoo J, Nichols A, Mammen J, Calvo I, Song JC, Worrell RT, Matlin K, Matthews JB (2003) Bryostatin-1 enhances barrier function in T84 epithelia through PKC-dependent regulation of tight junction proteins. Am J Physiol Cell Physiol 285(2):C300–C309. doi: 10.1152/ajpcell.00267.2002 CrossRefPubMedGoogle Scholar
  67. 67.
    Liu W, Wang P, Shang C, Chen L, Cai H, Ma J, Yao Y, Shang X, Xue Y (2014) Endophilin-1 regulates blood–brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway. Brain Res. doi: 10.1016/j.brainres.2014.05.022 Google Scholar
  68. 68.
    Thal SC, Luh C, Schaible EV, Timaru-Kast R, Hedrich J, Luhmann HJ, Engelhard K, Zehendner CM (2012) Volatile anesthetics influence blood–brain barrier integrity by modulation of tight junction protein expression in traumatic brain injury. PLoS One 7(12):e50752. doi: 10.1371/journal.pone.0050752 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Chen X, Duan XS, Xu LJ, Zhao JJ, She ZF, Chen WW, Zheng ZJ, Jiang GD (2014) Interleukin-10 mediates the neuroprotection of hyperbaric oxygen therapy against traumatic brain injury in mice. Neuroscience 266:235–243. doi: 10.1016/j.neuroscience.2013.11.036 CrossRefPubMedGoogle Scholar
  70. 70.
    McCaffrey G, Davis TP (2012) Physiology and pathophysiology of the blood–brain barrier: P-glycoprotein and occludin trafficking as therapeutic targets to optimize central nervous system drug delivery. J Investig Med Off Publ Am Fed Clin Res 60(8):1131–1140Google Scholar
  71. 71.
    Yang L, Shah KK, Abbruscato TJ (2012) An in vitro model of ischemic stroke. Methods Mol Biol 814:451–466. doi: 10.1007/978-1-61779-452-0_30 CrossRefPubMedGoogle Scholar
  72. 72.
    Effgen GB, Vogel EW 3rd, Lynch KA, Lobel A, Hue CD, Meaney DF, Bass CR, Morrison B 3rd (2014) Isolated primary blast alters neuronal function with minimal cell death in organotypic hippocampal slice cultures. J Neurotrauma 31(13):1202–1210. doi: 10.1089/neu.2013.3227 CrossRefPubMedGoogle Scholar
  73. 73.
    Arun P, Abu-Taleb R, Valiyaveettil M, Wang Y, Long JB, Nambiar MP (2013) Extracellular cyclophilin A protects against blast-induced neuronal injury. Neurosci Res 76(1–2):98–100. doi: 10.1016/j.neures.2013.02.009 CrossRefPubMedGoogle Scholar
  74. 74.
    Alves JL (2014) Blood–brain barrier and traumatic brain injury. J Neurosci Res 92(2):141–147. doi: 10.1002/jnr.23300 CrossRefPubMedGoogle Scholar
  75. 75.
    Kang JH, Asai D, Yamada S, Toita R, Oishi J, Mori T, Niidome T, Katayama Y (2008) A short peptide is a protein kinase C (PKC) alpha-specific substrate. Proteomics 8(10):2006–2011. doi: 10.1002/pmic.200701045 CrossRefPubMedGoogle Scholar
  76. 76.
    Teng JC, Kay H, Chen Q, Adams JS, Grilli C, Guglielmello G, Zambrano C, Krass S, Bell A, Young LH (2008) Mechanisms related to the cardioprotective effects of protein kinase C epsilon (PKC epsilon) peptide activator or inhibitor in rat ischemia/reperfusion injury. Naunyn Schmiedeberg's Arch Pharmacol 378(1):1–15. doi: 10.1007/s00210-008-0288-5 CrossRefGoogle Scholar
  77. 77.
    Barzilai A (2013) The interrelations between malfunctioning DNA damage response (DDR) and the functionality of the neuro-glio-vascular unit. DNA Repair 12(8):543–557. doi: 10.1016/j.dnarep.2013.04.007 CrossRefPubMedGoogle Scholar
  78. 78.
    Adelson PD, Fellows-Mayle W, Kochanek PM, Dixon CE (2013) Morris water maze function and histologic characterization of two age-at-injury experimental models of controlled cortical impact in the immature rat. Childs Nerv Syst CHNS Off J Int Soc Pediatr Neurosurg 29(1):43–53. doi: 10.1007/s00381-012-1932-4 CrossRefGoogle Scholar
  79. 79.
    Glushakova OY, Johnson D, Hayes RL (2014) Delayed increases in microvascular pathology after experimental traumatic brain injury are associated with prolonged inflammation, blood–brain barrier disruption, and progressive white matter damage. J Neurotrauma. doi: 10.1089/neu.2013.3080 PubMedGoogle Scholar
  80. 80.
    Lucke-Wold BP, Turner RC, Logsdon AF, Bailes JE, Huber JD, Rosen CL (2014) Linking traumatic brain injury to chronic traumatic encephalopathy: identification of potential mechanisms leading to neurofibrillary tangle development. J Neurotrauma. doi: 10.1089/neu.2013.3303 PubMedPubMedCentralGoogle Scholar
  81. 81.
    Wu J, Pajoohesh-Ganji A, Stoica BA, Dinizo M, Guanciale K, Faden AI (2012) Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion. J Neuroinflammation 9:169. doi: 10.1186/1742-2094-9-169 PubMedPubMedCentralGoogle Scholar
  82. 82.
    Stein TD, Alvarez VE, McKee AC (2014) Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel. Alzheimers Res Ther 6(1):4. doi: 10.1186/alzrt234 CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Turner RC, Lucke-Wold BP, Robson MJ, Omalu BI, Petraglia AL, Bailes JE (2012) Repetitive traumatic brain injury and development of chronic traumatic encephalopathy: a potential role for biomarkers in diagnosis, prognosis, and treatment? Front Neurol 3:186. doi: 10.3389/fneur.2012.00186 PubMedGoogle Scholar
  84. 84.
    Marcelo A, Bix G (2014) The potential role of perlecan domain V as novel therapy in vascular dementia. Metab Brain Dis. doi: 10.1007/s11011-014-9576-6 PubMedGoogle Scholar
  85. 85.
    Lanz TV, Becker S, Osswald M, Bittner S, Schuhmann MK, Opitz CA, Gaikwad S, Wiestler B, Litzenburger UM, Sahm F, Ott M, Iwantscheff S, Grabitz C, Mittelbronn M, von Deimling A, Winkler F, Meuth SG, Wick W, Platten M (2013) Protein kinase Cbeta as a therapeutic target stabilizing blood–brain barrier disruption in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 110(36):14735–14740. doi: 10.1073/pnas.1302569110 CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    De Bock M, Decrock E, Wang N, Bol M, Vinken M, Bultynck G, Leybaert L (2014) The dual face of connexin-based astroglial Ca communication: a key player in brain physiology and a prime target in pathology. Biochim Biophys Acta. doi: 10.1016/j.bbamcr.2014.04.016 Google Scholar
  87. 87.
    Naviaux RK (2014) Metabolic features of the cell danger response. Mitochondrion 16:7–17. doi: 10.1016/j.mito.2013.08.006 CrossRefPubMedGoogle Scholar
  88. 88.
    Eckert A, Nisbet R, Grimm A, Gotz J (2013) March separate, strike together - role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer's disease. Biochim Biophys Acta. doi: 10.1016/j.bbadis.2013.08.013 Google Scholar
  89. 89.
    Kamat PK, Rai S, Swarnkar S, Shukla R, Nath C (2014) Molecular and cellular mechanism of okadaic acid (OKA)-induced neurotoxicity: a novel tool for Alzheimer's disease therapeutic application. Mol Neurobiol. doi: 10.1007/s12035-014-8699-4 PubMedCentralGoogle Scholar
  90. 90.
    Ekinci FJ, Shea TB (1997) Selective activation by bryostatin-1 demonstrates unique roles for PKC epsilon in neurite extension and tau phosphorylation. Int J Dev Neurosci Off J Int Soc Dev Neurosci 15(7):867–874CrossRefGoogle Scholar
  91. 91.
    Barnes DE, Kaup A, Kirby KA, Byers AL, Diaz-Arrastia R, Yaffe K (2014) Traumatic brain injury and risk of dementia in older veterans. Neurology 83(4):312–319. doi: 10.1212/WNL.0000000000000616 CrossRefPubMedPubMedCentralGoogle Scholar

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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