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Mechanisms of calcium-mediated axonal injury in the immature brain
Dissertation   Open access

Mechanisms of calcium-mediated axonal injury in the immature brain

Ann Mae DiLeonardi
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2012
DOI:
https://doi.org/10.17918/00000656
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Abstract

Neurosciences
Traumatic brain injury (TBI) is a leading cause of death and disability in the pediatric population, with infants and children less than 4 years of age exhibiting higher morbidity and mortality when compared to older children and adults. The pathophysiologic hallmark of pediatric TBI is diffuse axonal injury (DAI). In animals, DAI is manifested as traumatic axonal injury (TAI), which results from a combination of mechanoporation of the axolemma, focal loss of microtubules, ionic dysregulation, impaired axonal transport (IAT) and neurofilament compaction (NFC). Diffuse brain injury in the 17-day-old immature rat resulted in neurofilament compaction and dephosphorylated neurofilaments which occurred independently with impaired axonal transport acutely post-injury. In addition, we observed a decrease in total protein of all three neurofilament subunits and axonal degeneration. These structural deficits were accompanied by deficits in compound action potential (CAP) of both myelinated and unmyelinated fibers in the corpus callosum between 1 and 14 days. In specific aim 1, we tested the hypothesis that inhibition of the calcium-dependent phosphatase, calcineurin, using FK506 would attenuate axonal injury. We observed that FK506 significantly attenuated the injury-induced accumulations of total NF200 and dephosphorylated NF200 at 3 days (p<0.001) and axonal degeneration at 3 and 7 days post-injury (p<0.01), but did not affect the decrease in NF200 protein levels or impaired axonal transport. FK506 had no effect on CAP deficits at 3 days post-injury, but exacerbated the deficit in only the myelinated fibers at 7 days. In aim 2, we tested the hypothesis that inhibition of the calcium-activated protease, calpain, using MDL28170 would attenuate axonal injury. We observed that treatment with MDL28170 significantly attenuated calpain activation; however, it was unable to decrease injury-induced tau proteolysis, impaired axonal transport, neurofilament compaction, axonal degeneration, or impaired axonal function. Finally in aim 3, we evaluated the route of entry of calcium into axons following diffuse brain injury. Pre-injury treatment with either the NMDAR antagonist, ifenprodil, or the AMPAR antagonist, NBQX, had no effect on the extent of TAI, suggesting that excitotoxicity may not be a primary mechanism underlying TAI. Treatment with the sodium-calcium exchange inhibitor, KB-R7943, was sufficient to decrease the amount of calpain-induced spectrin breakdown at 1 day post-injury; whereas, KB-R7943-treatment did not show success at attenuating tau proteolysis or axonal dysfunction.

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