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Final Dis-QA 4-28-2017.pdf (17.88 MB)
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Role of Cofilin in Intracerebral Hemorrhage: in Vitro and in Vivo Studies
Author Info
Alhadidi, Qasim Mahmood
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1493416784475914
Abstract Details
Year and Degree
2017, Doctor of Philosophy, University of Toledo, Medicinal Chemistry.
Abstract
Intracerebral hemorrhage (ICH) is a devastating form of stroke with high mortality and morbidity. It is more severe than ischemic stroke and half of the patients die during the first month following the attack. Furthermore, patients who survive the attack undergo major neurological impairments. However, the treatment of ICH is limited to supportive care and there is no ICH specific therapy. The pathogenesis of ICH injury is complex and it involves primary insult triggered by hematoma mass effect and secondary insult triggered by brain tissue response to hematoma constituents. Since trials targeting primary injury have been ineffective, secondary injury mechanisms such as neuroinflammation and oxidative stress may bring new therapeutic possibilities. Cofilin, a ubiquitous actin associated protein, was found to be involved in many neurodegenerative diseases. Disruption of cofilin dynamics leads to cofilin-actin rod formation in different cellular compartments initiating neuronal cell death and apoptosis. However, the role of cofilin in ICH remains unclear and needs further investigation. In the present study, the role of cofilin in ICH was investigated using in vitro and in vivo models. Both primary cortical neurons and a spontaneously immortalized microglial cell line were used in in vitro studies. In primary cortical neurons subjected to oxygen and glucose deprivation, an ischemia model, cofilin was found to be highly activated and resulted in neuronal apoptosis, which was significantly inhibited by cofilin knockdown using small interfering RNA (siRNA). In microglia, cofilin knockdown significantly inhibited LPS-induced microglial cell activation through antagonizing NF-¿B and JAK–STAT pathways. The release of proinflammatory mediators, microglial proliferation and microglial migration rates were significantly reduced by cofilin knockdown. In collagenase-induced ICH in mice, cofilin expression and phosphorylation was found to be significantly upregulated in the perihematomal area. Importantly, cofilin knockdown by using cofilin siRNA significantly reduced the volume of injury and improved the neurobehavioral deficits via combating oxidative/nitrosative stress and modulating neuroinflammation. In conclusion, disruption of cofilin dynamics during ICH is one of the important factors mediating ICH injury. The involvement of cofilin in neuronal apoptosis, glial cell activation and BBB disruption suggests its multifaceted physiological roles and the possibility that it may be used as a potential target for the development of therapeutic interventions for multifactorial diseases like ICH.
Committee
Zahoor Shah (Committee Chair)
Katherine Wall (Committee Member)
Hermann Von Grafenstein (Committee Member)
Frank Scott Hall (Committee Member)
Pages
201 p.
Subject Headings
Neurobiology
;
Neurosciences
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Citations
Alhadidi, Q. M. (2017).
Role of Cofilin in Intracerebral Hemorrhage: in Vitro and in Vivo Studies
[Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1493416784475914
APA Style (7th edition)
Alhadidi, Qasim.
Role of Cofilin in Intracerebral Hemorrhage: in Vitro and in Vivo Studies.
2017. University of Toledo, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1493416784475914.
MLA Style (8th edition)
Alhadidi, Qasim. "Role of Cofilin in Intracerebral Hemorrhage: in Vitro and in Vivo Studies." Doctoral dissertation, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1493416784475914
Chicago Manual of Style (17th edition)
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Document number:
toledo1493416784475914
Download Count:
388
Copyright Info
© 2017, all rights reserved.
This open access ETD is published by University of Toledo and OhioLINK.