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PhD (Doctor of Philosophy)
Date of Award
Committee Chair or Co-Chairs
Balvin H.L. Chua
Russell W. Brown, Richard M. Kostrzewa, Michelle M. Duffourc, Dennis M. Defoe
Stroke is the third leading cause of death and disability in the United States. At present, intravenous administration of tissue plasminogen activator (t-PA) is the only thrombolytic therapy approved by the FDA for the treatment of acute ischemic stroke. There are no other effective treatments available so far. The discovery of new drugs and new treatments for stroke to reduce mortality and disability is an urgent medical research priority. In this study, the protective effects and mechanisms of two novel agents Gly14 humanin (HNG) and necrostatin-1 (Nec-1) were examined. HNG, a highly potent neuropeptide against amyloid toxicity, exhibited anti-apoptotic properties on cerebral ischemia injury. HNG reduced infarct volume after ischemia/reperfusion injury with pre-treatment or post-treatment (i.c.v. and i.p.) in a middle cerebral artery occlusion model in mice and decreased neurological deficits induced by ischemia. The protection of HNG was mediated by inhibiting ERK activation and activating PI3K/Akt pathway. Inhibition of the PI3K/Akt pathway blocked the protective effects of HNG. Nec-1 is a specific inhibitor of necroptosis, a newly identified cell death, and was reported to reduce infarct volume even when it was administered at 6 h post-ischemia in a mouse stroke model. Interestingly, this small molecule protected against glutamate-induced oxidative toxicity in a hippocampal HT-22 cell line. It inhibited the translocation of apoptosis-inducing factor from the mitochondria to the nucleus, increased the cellular glutathione level, and decreased free radical formation after glutamate treatment. More importantly, Nec-1 inhibited BNIP3-mediated caspase-independent cell death. Cerebral ischemia/reperfusion injury involves the activation of different pathways that lead to neuronal cell death. Given this multifactorial pathnogenesis, it is possible that a cocktail of neuroprotective agents would be superior to monotherapy. In this study, a cocktail of HNG and Nec-1 was examined in vitro and in vivo. HNG and Nec-1 exerted synergistic neuroprotection on oxygen-glucose deprivation-induced cell death and cerebral ischemia/reperfusion injury. This study provided a new therapeutic strategy for the treatment of stroke by the combination of anti-apoptosis and anti-necroptosis therapy.
Dissertation - restricted
Xu, Xingshun, "Novel Protective Agents against Cerebral Ischemia/Reperfusion Injury." (2007). Electronic Theses and Dissertations. Paper 2054. https://dc.etsu.edu/etd/2054
Copyright by the authors.