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Dissertation
Mechanisms and prevention of axonal damage in response to mechanical trauma to cultured neurons
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2008
DOI:
https://doi.org/10.17918/etd-2760
Abstract
Diffuse axonal injury (DAI), a major component of traumatic brain injury, is a manifestation of microstructural cellular trauma and various ensuing neurochemical reactions that leads to secondary neuronal death. DAI is suggested to result from the initial increase in the membrane permeability caused by the mechanical forces acting on the axons. Permeability increases disturb ion balance and lead to cytoskeletal disruption resulting in the impairment of axonal transport. In this study, we present an in vitro neurotrauma model that reproduces important features of in vivo DAI such as membrane permeability changes, focal disruption of microtubules, impaired axonal transport, and focal axonal beading, the "hallmark" morphology of DAI. In addition, we show that the post-injury increase in the intracellular calcium ion concentration and subsequent calpain activity are the underlying phenomena in the neuropathological sequelae following mechanical injury. Interestingly, calcium and calpain activity are pronounced n focal "hot spots" that develop into axonal beads. Post-injury application of Poloxamer 188, a polymer known to reseal damaged membranes, successfully reduced mechanoporation, calpain activity, microtubule disruption, and axonal beading. These results suggest that membrane repair has a therapeutic potential in DAI. We have developed a spatiotemporal axon model to simulate post-injury calcium and calpain mechanisms. We show that calcium-dependent calpain activity depends on the amount of poration and is modulated by mitochondria and calpain activation dynamics.
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Details
- Title
- Mechanisms and prevention of axonal damage in response to mechanical trauma to cultured neurons
- Creators
- Devrim Kilinc - DU
- Contributors
- Kenneth A. Barbee (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 2760; 991014632526604721