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The Journal of Neuroscience, March 22, 2006, 26(12):3130-3140; doi:10.1523/JNEUROSCI.5119-05.2006

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Neurobiology of Disease
Mechanoporation Induced by Diffuse Traumatic Brain Injury: An Irreversible or Reversible Response to Injury?

Orsolya Farkas,^1,2 Jonathan Lifshitz,¹ and John T. Povlishock¹

¹Department of Anatomy and Neurobiology, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, Virginia 23298, and ²Department of Neurosurgery, Medical Faculty of Pecs University, H-7623 Pecs, Hungary

Correspondence should be addressed to Dr. John T. Povlishock, Department of Anatomy and Neurobiology, Medical College of Virginia Campus of Virginia Commonwealth University, P.O. Box 980709, Richmond, VA 23298. Email: jtpovlis{at}vcu.edu

Diffuse traumatic brain injury (DTBI) is associated with neuronal plasmalemmal disruption, leading to either necrosis or reactive change without cell death. This study examined whether enduring membrane perturbation consistently occurs, leading to cell death, or if there is the potential for transient perturbation followed by resealing/recovery. We also examined the relationship of these events to calpain-mediated spectrin proteolysis (CMSP). To assess plasmalemmal disruption, rats (n = 21) received intracerebroventricular infusion 2 h before DTBI of a normally excluded 10 kDa fluorophore-labeled dextran. To reveal plasmalemmal resealing or enduring disruption, rats were infused with another labeled dextran 2 h (n = 10) or 6 h (n = 11) after injury. Immunohistochemistry for the 150 kDa spectrin breakdown product evaluated the concomitant role of CMSP. Neocortical neurons were followed with confocal and electron microscopy. After DTBI at 4 and 8 h, 55% of all tracer-flooded neurons contained both dextrans, demonstrating enduring plasmalemmal leakage, with many demonstrating necrosis. At 4 h, 12.0% and at 8 h, 15.7% of the dual tracer-flooded neurons showed CMSP, yet, these demonstrated less advanced cellular change. At 4 h, 39.0% and at 8 h, 24.4% of all tracer-flooded neurons revealed only preinjury dextran uptake, consistent with membrane resealing, whereas 7.6 and 11.1%, respectively, showed CMSP. At 4 h, 35% and at 8 h, 33% of neurons demonstrated CMSP without dextran flooding. At 4 h, 5.5% and at 8 h, 20.9% of tracer-flooded neurons revealed only postinjury dextran uptake, consistent with delayed membrane perturbation, with 55.0 and 35.4%, respectively, showing CMSP. These studies illustrate that DTBI evokes evolving plasmalemmal changes that highlight mechanical and potential secondary events in membrane poration.

Key words: diffuse traumatic brain injury; neuron; dextrans; membrane disruption; membrane resealing; calpain

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Received Aug. 18, 2005; revised Jan. 16, 2006; accepted Feb. 8, 2006.

Correspondence should be addressed to Dr. John T. Povlishock, Department of Anatomy and Neurobiology, Medical College of Virginia Campus of Virginia Commonwealth University, P.O. Box 980709, Richmond, VA 23298. Email: jtpovlis{at}vcu.edu

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