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Stroke Study: Novel Animal Models and Innovative Treatment Strategy

Yu, Xinge
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1450735023

Abstract Details

2016, Doctor of Philosophy (PhD), Ohio University, Biological Sciences (Arts and Sciences).
As one of the leading causes of death and long-term disability, stroke brings detrimental burden to its patients and the society. The most common subtype of stroke is ischemic stroke. Current treatment for ischemic stroke is limited. The only FDA approved drug is tissue plasminogen activator (tPA). The application of tPA is restricted within 4.5 hours of stroke onset, due to its severe side effects and broad contraindications. The lethal side effect of tPA is hemorrhage. The usage of tPA and its therapeutic effect has to be compromised to avoid hemorrhage. Studies have been proposing that Zn2+ accumulation has deleterious effect in ischemic neuronal damage, and reducing intracellular Zn2+ overload by Zn2+ chelation improve neuronal survival from cerebral ischemia. In this study, the therapeutic effect of Zn2+ chelation is investigated not only in mice, but also in a newly developed zebrafish model. Severe hypoxia was performed to induce a hypoxic-ischemic brain injury on zebrafish, to mimic the global cerebral stroke in a cardiac arrest. A self-designed chamber was used to perform stable and effective hypoxia. The brain injury was quantified by histological staining of the brain, and the overall survival and behavioral changes of zebrafish after hypoxia. Photothrombotic method was adopted and modified to develop adult zebrafish as a model for focal thrombotic stroke. Rose Bengal was intraperitoneally injected to the zebrafish and a light probe was placed on the optic tectum of the brain. Brain damage was quantified by 2,3,5-Triphenyltetrazolium chloride (TTC) staining and overall recovery. Treatment of tPA was used to confirm thrombosis-induced brain injuries and the feasibility of using zebrafish model to screen thrombolytic candidates. In vitro experiment, spectrophotometry was used to quantify blood clot-lysis (thrombolysis). Thrombosis model in vivo was achieved by photothrombotic method on the mouse femoral artery. The artery reperfusion induced by tPA was monitored under microscope and quantified by ImagePro. Results of this study show that adult zebrafish are sensitive to hypoxia. Detectable brain injury can be achieved by 8 minutes of severe hypoxia. Longer time of hypoxic treatment leads to moving disability and mortality of zebrafish. Zn2+ chelation improves neuronal viability under oxygen deprivation, and therefore increases the behavioral recovery and overall survival rate. During thrombolysis, the blood clot releases high concentration of Zn2+. Data suggest that increase of Zn2+ around the thrombosis reduces tPA-induced thrombolysis. Zn2+ chelation, when combined with tPA, increase the overall thrombolysis in vitro and the rate of successful reperfusion in vivo. Moreover, the application of Zn2+ chelation improves efficacy and potency of tPA-induced thrombolysis. In conclusion, Zn2+ chelation has shown promoting effect in neuronal rescue, and also in assisting thrombolysis during thrombotic stroke. It can be a treatment combining with tPA to improve successful reperfusion and reduces tPA-induced cytotoxicity. Taken together, Zn2+ chelation is promising to be used to improve outcomes of stroke and cardiovascular occlusion.
Yang Li (Advisor)
Gary Cordingley (Committee Member)
Robert Colvin (Committee Member)
Daewoo Lee (Committee Member)
185 p.
Biomedical Research; Neurosciences
stroke; animal models; zebrafish; neuroprotective agents; metal ion; zinc; tPA; thrombolysis

Recommended Citations

Citations

  • Yu, X. (2016). Stroke Study: Novel Animal Models and Innovative Treatment Strategy [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1450735023

    APA Style (7th edition)

  • Yu, Xinge. Stroke Study: Novel Animal Models and Innovative Treatment Strategy. 2016. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1450735023.

    MLA Style (8th edition)

  • Yu, Xinge. "Stroke Study: Novel Animal Models and Innovative Treatment Strategy." Doctoral dissertation, Ohio University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1450735023

    Chicago Manual of Style (17th edition)

ohiou1450735023
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This open access ETD is published by Ohio University and OhioLINK.