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Dissertation
Secreted phospholipase A2 and spinal cord injury
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2012
DOI:
https://doi.org/10.17918/00000606
Abstract
Spinal cord injury (SCI) is followed by long-lasting and devastating secondary processes including inflammation, free radical-induced cell death and glutamate excitotoxicity. A candidate molecule that could serve as a common mediator for all these processes is secreted phospholipase A2 (sPLA2). sPLA2 enzymes hydrolyze membrane and circulating lipids, leading to the generation of mediators like lysophosphatidylcholine and arachidonic acid, well known for their involvement in inflammation, immunity and cell death in several organ systems. However, the roles of sPLA2 enzymes in the secondary degeneration after SCI remain unclear. Therefore in the present work, we investigated the roles of sPLA2s in spinal cord contusion utilizing CHEC-9, a neuroprotective peptide and potent sPLA2 inhibitor. The ability of this peptide to block the specific cellular actions of sPLA2 was examined using homogeneous neuronal cells (SY5Y) and monocytic cells (HL-60) in vitro. sPLA2 inhibition provided direct protection to differentiated SY5Y neuronal cells and their processes in response to several forms of cellular stress and independently attenuated different aspects of macrophage differentiation in HL-60 cultures without influencing cell survival. Then the specific phospholipids that are targeted by sPLA2 enzymes were investigated in vivo following cervical spinal cord contusion. sPLA2 inhibition selectively rescued several species of phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol but not phosphatidylcholine. This selectivity may partly be due to the substrate preference of this peptide illustrated in this paper by the mixed liposome assay. Finally, we examined the role of sPLA2s in secondary injury including inflammatory responses and behavior after spinal cord injury. We discovered that sPLA2 inhibition attenuated the cellular and molecular inflammatory responses, protected white matter and motor neurons and accelerated forelimb locomotion recovery in the acute phase of injury. We conclude that sPLA2 enzymes organize a cascade of changes comprising both cell degeneration and inflammation, and inhibition of the enzyme by the CHEC-9 peptide influences these parameters as well as the time course of functional recovery following SCI. Furthermore, these studies provide the impetus to investigate the possibility of long-lasting behavioral recovery following the injury by extending the peptide treatment regimens or applying the peptide in combinational therapies.
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Details
- Title
- Secreted phospholipase A2 and spinal cord injury
- Creators
- Shuyan Chen
- Contributors
- Timothy J. Cunningham (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xii, 146 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; College of Medicine; Drexel University
- Other Identifier
- 991014970317704721