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To investigate neuroprotective mechanism in female brain

Tulsulkar, Jatin
http://orcid.org/0000-0001-5981-4330
http://rave.ohiolink.edu/etdc/view?acc_num=mco1446042789

Abstract Details

2015, Doctor of Philosophy (PhD), University of Toledo, Pharmaceutical Sciences (Medicinal Chemistry).
It is well known that gender differences exist in the experimental or clinical stroke with respect to the tissue damage and the loss of functional outcome. We have previously reported neuroprotective properties of Ginkgo biloba/EGb 761® (EGb 761) in transient and permanent mouse models of brain ischemia in male mice and the mechanism of neuroprotection was attributed to the upregulation of the HO1/Wnt pathway. Here, we sought to investigate the novel hypothesis, whether neuroprotection by EGb 761 in ovariectomized (OVX) female mice is mediated by HO1/Wnt upregulation in a model of permanent cerebral ischemia. The OVX mice pretreated with EGb 761 for 7 days were subjected to permanent ischemia at day 8 and sacrificed on day 14. Infarct volume analysis showed that EGb 761 pretreated OVX mice had lower infarct volume, lower neurological deficits and improved motor skills as compared to OVX female vehicle mice. Protein analysis studies demonstrated that neuroprotection in EGb 761 pretreatment OVX group is not mediated by HO1/Wnt pathway. Furthermore EGb 761 pretreatment group demonstrated overexpression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide (eNOS). In addition, increased expression of TNF-a in the vehicle group was observed to be comparatively lower in EGb 761 pretreated OVX group. These results suggest that the neuroprotective effect of EGb 761 in females is not associated with the activation and upregulation of HO1/Wnt pathway. To further understand the cell death mechanism involved, we studied expression levels of apoptotic protein cleaved caspase-3 and caspase-8 which were found to be significantly elevated in the Veh/OVX group as compared to the EGb 761/OVX group. We previously showed that EGb 761 post and pretreatment enhances neurogenesis by increasing the number of neural stem progenitor cells (NSPC’s) in male mice 7 days following permanent ischemia, similarly in this study we demonstrated that in absence of ovarian hormone estrogen, EGb 761 increased NSPC’s 7 days after ischemia. To test whether EGb 761 in absence of estrogen activates another gonadal steroid androgen, luciferase assay and immunofluorescent studies suggested that EGb 761 significantly binds and results in activation of androgen receptor (AR) in female brain. Taken together these results suggest that the possible mechanism of EGb 761 mediated neuroprotection in females following permanent ischemia is independent of HO1/Wnt signaling and via caspase dependent pathway and neurogenesis.
Zahoor Shah, PhD. (Committee Chair)
Hermann von Grafenstein, PhD. (Committee Member)
Amanda Bryant-Friedrich, PhD. (Committee Member)
Ming Cheh Liu, PhD. (Committee Member)
93 p.
Biology; Neurosciences
Sexual differences, Female brain, Stroke

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Citations

  • Tulsulkar, J. (2015). To investigate neuroprotective mechanism in female brain [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1446042789

    APA Style (7th edition)

  • Tulsulkar, Jatin. To investigate neuroprotective mechanism in female brain. 2015. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1446042789.

    MLA Style (8th edition)

  • Tulsulkar, Jatin. "To investigate neuroprotective mechanism in female brain." Doctoral dissertation, University of Toledo, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=mco1446042789

    Chicago Manual of Style (17th edition)

mco1446042789
381
© , some rights reserved.Creative Commons License To investigate neuroprotective mechanism in female brain by Jatin Tulsulkar is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.