Date of Award
Restricted Access Dissertation
Doctor of Philosophy
Field of Study
Graduate School of Biomedical Sciences
James W. Simpkins
Yi Wen, Mentor: James W. Simpkins. Neurodegeneration and Neuroprotection in Transient Cerebral Ischemic Stroke. Doctor of Philosophy (Biomedical Science), July 2004, pp287, 2 tables, 44 illustrations, 88 titles. Stroke is the third leading cause of mortality and morbidity in the U.S., with over 750,000 cases per year. Post-stroke symptoms include debilitating chronic neurological complications, which result from neuronal damage. Above 80% of strokes are thrombotic, and drugs like tissue Plasminogen Activator (t-PA) have been clinically applied to dissolve the clot and reestablish blood flow to the affected area. Animal models for stroke have provided much new information on the etiology of the neuronal damage in stroke. Experimental MCA occlusion has been successfully used to produce focal ischemic lesions in rodents. This procedure causes a unilateral ischemic area that typically involves the basal ganglion and frontal, parietal and temporal cortical areas. Interestingly, both early necrotic-type cell death and delayed apoptotic cells death have been described following an ischemic event. In spite of the intensive research in the stroke, effective therapies other than t-PA treatment are not yet available. The current study includes two parts, the first part includes the effects of a sex steroid hormone, estrogen, on several aspects of stroke and other neurotoxicity, including oxidative damage and post-ischemic inflammatory response. Estrogen’s neuroprotective effects have been well demonstrated both in vitro and in vivo. Our studies in this part include the investigation of several potential mechanisms of estrogen’s potent neuroprotective activity that include the activation of neuronal isoform of nitric oxide synthase (nNos), and suppression of NFκB, and its corresponding signal transduction pathways for post-ischemic inflammation. We observed that estrogen induces nNos activation rapidly, NO is highly protective at low concentrations, NOS inhibitors can block the potent neuroprotection of estrogen. At least, part of estrogen’s neuroprotection is mediated by rapid nNOS activation in a way that is independent of estrogen’s traditional transcriptional activity. Estrogen was very effective at suppressing the post-ischemic inflammation, reflected by the suppression of NFκB activity, reduction of IκB phosphorylation and iNOS expression. The other part of the studies includes the research that correlates stroke with neurodegenerative diseases. This part of research includes the investigation of the effects of ischemic stroke on APP processing enzymes, α and β secretases. Ischemic injury induced neurotoxicity caused the hyperphosphorylation of a microtubule protein tau, which is one of the pathological hallmarks of Alzheimer’s Disease. Tau hyperphosphorylation appears to be related with the activation/de-regulation of Cdk5, a cyclin dependent kinase, in post-mitotic neurons. We also observed the induction of aberrant cell cycle reentry, which is also a characteristic feature of many neurodegenerative diseases. This is also related with Cdk5 activation/de-regulation.
"Neurodegeneration and Neuroprotection in Transient Cerebral Ischemic Stroke" Fort Worth, Tx: University of North Texas Health Science Center;