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dc.contributor.authorAlhusban, Ahmed Yusuf Ahmed
dc.date.accessioned2014-03-04T21:04:54Z
dc.date.available2014-03-04T21:04:54Z
dc.date.issued2013-08
dc.identifier.otheralhusban_ahmed_y_201308_phd
dc.identifier.urihttp://purl.galileo.usg.edu/uga_etd/alhusban_ahmed_y_201308_phd
dc.identifier.urihttp://hdl.handle.net/10724/28958
dc.description.abstractDespite significant improvement in our understanding of stroke pathophysiology and management, it is still a leading cause of death and disability worldwide. Interventions directed toward blood pressure reduction have proven beneficial in reducing stroke incidence and recurrence. Extrapolating these possible beneficial effects to the acute phase has been avoided, which limits exploitation of possible blood pressure independent effects of some antihypertensive agents. BDNF has been demonstrated to improve stroke outcome, by its dual ability to induce angiogenesis and neurogenesis. The aim of this work is to assess the interaction between blood pressure reduction with candesartan and BDNF/TrkB mediated improvement in functional outcome after stroke. To achieve this aim, the interaction between candesartan and BDNF was assessed in normotensive and hypertensive animals and in human cerebrovascular endothelial cells (hCMECs). Furthermore, the involvement of BDNF in candesartan induced long-term functional outcome improvement was assessed using shRNA mediated BDNF knockdown in normotensive animals. Additionally, the ability of candesartan to affect BDNF/TrkB activity after stroke was evaluated in hypertensive animals. To dissect the involvement of blood pressure reduction in candesartan mediated effects, a sub-hypotensive dose of candesartan and intervention to override candesartan induced hypotensive effect was also used. Candesartan was found to positively interact with BDNF/TrkB both in vitro and in vivo. This interaction was detected in normotensive and hypertensive animals, without regard to whether they have been exposed to cerebral ischemia or not. Additionally, this positive interaction was demonstrated to be independent of its hypotensive effect. Interestingly, the angiogenic effect of candesartan was found to be mediated by BDNF/TrkB activity which was shown to be modulated by AT2 signaling. In conclusion, the positive interaction between candesartan and BDNF/TrkB is not dependent on its hypotensive effect.
dc.languageeng
dc.publisheruga
dc.rightspublic
dc.subjectstroke
dc.subjecthypertension
dc.subjectBDN
dc.subject, angiotensin receptor blockers
dc.subjectcandesartan
dc.subjectangiogenesis
dc.subjectfunctional outcome
dc.subjectneurovascular protection
dc.subjectAT2
dc.titleImproving stroke outcome through increasing the activity of the BDNF/TrkB system
dc.typeDissertation
dc.description.degreePhD
dc.description.departmentClinical and Administrative Pharmacy
dc.description.majorPharmacy
dc.description.advisorSusan Fagan
dc.description.committeeSusan Fagan
dc.description.committeeSomanath Shenoy
dc.description.committeeWilliam D. Hill
dc.description.committeeAdviye Ergul
dc.description.committeeAzza El-Remessy


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