Pathological Mechanisms of Retinal Ischemia/Reperfusion Injury and Potential Targets of Neuroprotection

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dc.contributor.advisorClark, Abbot F.
dc.contributor.committeeMemberPang, Iok-Hou
dc.contributor.committeeMemberKrishnamoorthy, Raghu R.
dc.creatorSilverman, Sean M.
dc.date.accessioned2019-08-22T21:29:30Z
dc.date.available2019-08-22T21:29:30Z
dc.date.issued2015-12-01
dc.date.submitted2016-01-07T09:06:06-08:00
dc.description.abstractNeurodegenerative diseases trigger a cascade of pathological mediators including significant accumulation of reactive oxygen species (ROS) and chronic neuroinflammation resulting in widespread neuronal loss. We can effectively mimic these changes in a mouse model of retinal ischemia/reperfusion (I/R) injury. Herein we demonstrate retinal I/R leads to chronic upregulation of C1q expression accompanied by similar long-term activation of microglia and astrocytes, as well as a significant increase in retinal ROS. These changes resulted in morphological and functional degeneration. In addition, we identified the neuroprotective potential of modulating changes in C1q and superoxide by genetic and pharmacological methods. In the retina I/R injury resulted in significant increases in C1q expression, glial activation and cell density by day 3 compared to controls. These changes continued to increase and were sustained through our entire 28 day time course. Similar effects from injury were observed in the superior colliculus (SC), one of the primary visual centers in the brain of rodents. Surprisingly, hemispheres corresponding to both injured and noninjured eyes displayed signs of chronic neuroinflammation by day 21. Using the chemilluminescent compound L-012 we demonstrated a novel method for non-invasive in vivo detection of superoxide in the eye as early as 24 hours post injury. These findings were confirmed with dihydroethidium (DHE) in the retina. Our previous work has characterized inner retinal thinning, loss of retinal ganglion cells (RGCs), and suppression of b-wave amplitudes due to I/R injury. Using C1qa-deficient mice, we show complete morphological protection and ablation of reactive microgliosis. However, astrocytes were unaffected by deletion of C1q, and retinal function was only partially preserved. Two superoxide inhibitors, Apocynin and Tempol, significantly reduced L-012 chemilluminescence 24 and 48 hours after injury. Further, Apocynin treatment completely protected against morphological degeneration in the retina and significantly rescued functional deficits. In conclusion, this study demonstrates the therapeutic potential of modulating either C1q or superoxide for neuroprotection following injury or diseases where they are implicated in pathological loss.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/29372
dc.language.isoen
dc.provenance.legacyDownloads22
dc.subjectMedical Sciences
dc.subjectMedicine and Health Sciences
dc.subjectretinal ischemia
dc.subjectC1q
dc.subjectneuroinflammation
dc.titlePathological Mechanisms of Retinal Ischemia/Reperfusion Injury and Potential Targets of Neuroprotection
dc.typeDissertation
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineVisual Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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