Journal
MOLECULAR NEUROBIOLOGY
Volume 52, Issue 3, Pages 1119-1134Publisher
SPRINGER
DOI: 10.1007/s12035-014-8902-7
Keywords
Blood brain barrier; Bryostatin-1; Protein kinase C; Tight junction proteins
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Funding
- West Virginia University Health Sciences Center Office of Research and Graduate Education
- WVU Department of Neurosurgery
- NIH [GM08174]
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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, PKC alpha, PKC delta, and PKC epsilon, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKC alpha levels back toward control levels (t = 4.559, p < 0.01) and increased the neuroprotective isozyme PKC epsilon (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.
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