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postgraduate thesis: Targeting caveolin-1 as a therapeutic approach to prevent blood-brain barrier breakdown in ischemic stroke : from mechanism to isoflavones treatment

TitleTargeting caveolin-1 as a therapeutic approach to prevent blood-brain barrier breakdown in ischemic stroke : from mechanism to isoflavones treatment
Authors
Advisors
Advisor(s):Chung, SKShen, J
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Gu, Y. [顧勇]. (2014). Targeting caveolin-1 as a therapeutic approach to prevent blood-brain barrier breakdown in ischemic stroke : from mechanism to isoflavones treatment. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5194788
AbstractOur group previously reported that caveolin-1 (cav-1) was down-regulated by nitric oxide (NO) during cerebral ischemia and reperfusion (I/R). However, the role of cav-1 in regulating blood-brain barrier (BBB) permeability is unclear yet. This study aims to address whether the loss of cav-1 induced by NO production affects BBB permeability. Data showed that the expression of cav-1 in isolated cortical microvessels was down-regulated in ischemia-reperfused rat brains subjected to middle cerebral artery occlusion (MCAO). Treatment of NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, reserved cav-1 expression, inhibited matrix metalloproteinases (MMPs) activity and reduced the BBB permeability. Moreover, cav-1 knockdown remarkably increased MMPs activity in the culture medium of brain microvascular endothelial cells. Cav-1 deficiency mice displayed higher MMPs activity and BBB permeability than that of the wild-type mice. Interestingly, the effects of L-NAME on MMPs activity and BBB permeability were partly reversed in cav-1 deficiency mice. These results suggest that cav-1 plays important roles in regulating MMPs activity and BBB permeability in cerebral I/R injury. After completing the mechanism study, I investigated the potential drug candidate that targets cav-1 for protecting BBB and neuronal damage during cerebral I/R. Results showed that calycosin, an isoflavones from Astragali Radix, up-regulated the expression of cav-1 and inhibited MMPs activity, and decreased the BBB permeability in the MCAO ischemia-reperfused rat brains. I further investigated the neuroprotective effects of isoflavones of Astragali Radix, with in vitro oxygen glucose deprivation (OGD) model and in vivo cerebral ischemia-reperfusion models. In addition to calycosin and formononetin, two major isoflavones in Astragali Radix, daidzein was also included because it is a metabolite of formononetin after absorption. Results showed that all three isoflavones decreased infarction volume and neurological scores in MCAO rats and dose-dependently attenuated neuronal death induced by L-glutamate treatment and oxygen-glucose deprivation plus reoxygenation (OGD/RO). The neuroprotective effects were inhibited by estrogen receptors (ER) antagonist ICI 182,780. Interestingly, combine treatment of isoflavones displayed synergistic effects in both OGD/RO and L-glutamate induced neuronal injury models, as well as in MCAO cerebral ischemia-reperfusion rat brains. Mechanistically, estrogen receptor antagonist partly reduced the synergism in these models. PI3K/Akt activation was synergistically induced by treatment of those isoflavones simultaneously. In summary, cav-1 could be a potential therapeutic target for protecting the BBB in the treatment of cerebral I/R injury. Major findings in this thesis include: 1) Cav-1 plays an important role in maintaining BBB integrity through inhibition of MMPs activity. NO induced MMPs activities and BBB leakage are partially mediated by the down-regulation of cav-1 during cerebral I/R injury. 2) Calycosin treatment reserved cav-1 expression and reduced BBB permeability. 3) Isoflavones synergistically protected neurons against I/R-induced neuronal insults both in vitro and in vivo. The works provide a valuable step towards the clarification of the physiological and pathophysiological functions of cav-1, and a new clue for developing isoflavones as agents targeting cav-1 for the prevention or treatment of ischemic stroke.
DegreeDoctor of Philosophy
SubjectMembrane proteins
Cerebrovascular disease - Treatment
Isoflavones
Dept/ProgramChinese Medicine
Persistent Identifierhttp://hdl.handle.net/10722/197561

 

DC FieldValueLanguage
dc.contributor.advisorChung, SK-
dc.contributor.advisorShen, J-
dc.contributor.authorGu, Yong-
dc.contributor.author顧勇-
dc.date.accessioned2014-05-27T23:16:44Z-
dc.date.available2014-05-27T23:16:44Z-
dc.date.issued2014-
dc.identifier.citationGu, Y. [顧勇]. (2014). Targeting caveolin-1 as a therapeutic approach to prevent blood-brain barrier breakdown in ischemic stroke : from mechanism to isoflavones treatment. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5194788-
dc.identifier.urihttp://hdl.handle.net/10722/197561-
dc.description.abstractOur group previously reported that caveolin-1 (cav-1) was down-regulated by nitric oxide (NO) during cerebral ischemia and reperfusion (I/R). However, the role of cav-1 in regulating blood-brain barrier (BBB) permeability is unclear yet. This study aims to address whether the loss of cav-1 induced by NO production affects BBB permeability. Data showed that the expression of cav-1 in isolated cortical microvessels was down-regulated in ischemia-reperfused rat brains subjected to middle cerebral artery occlusion (MCAO). Treatment of NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, reserved cav-1 expression, inhibited matrix metalloproteinases (MMPs) activity and reduced the BBB permeability. Moreover, cav-1 knockdown remarkably increased MMPs activity in the culture medium of brain microvascular endothelial cells. Cav-1 deficiency mice displayed higher MMPs activity and BBB permeability than that of the wild-type mice. Interestingly, the effects of L-NAME on MMPs activity and BBB permeability were partly reversed in cav-1 deficiency mice. These results suggest that cav-1 plays important roles in regulating MMPs activity and BBB permeability in cerebral I/R injury. After completing the mechanism study, I investigated the potential drug candidate that targets cav-1 for protecting BBB and neuronal damage during cerebral I/R. Results showed that calycosin, an isoflavones from Astragali Radix, up-regulated the expression of cav-1 and inhibited MMPs activity, and decreased the BBB permeability in the MCAO ischemia-reperfused rat brains. I further investigated the neuroprotective effects of isoflavones of Astragali Radix, with in vitro oxygen glucose deprivation (OGD) model and in vivo cerebral ischemia-reperfusion models. In addition to calycosin and formononetin, two major isoflavones in Astragali Radix, daidzein was also included because it is a metabolite of formononetin after absorption. Results showed that all three isoflavones decreased infarction volume and neurological scores in MCAO rats and dose-dependently attenuated neuronal death induced by L-glutamate treatment and oxygen-glucose deprivation plus reoxygenation (OGD/RO). The neuroprotective effects were inhibited by estrogen receptors (ER) antagonist ICI 182,780. Interestingly, combine treatment of isoflavones displayed synergistic effects in both OGD/RO and L-glutamate induced neuronal injury models, as well as in MCAO cerebral ischemia-reperfusion rat brains. Mechanistically, estrogen receptor antagonist partly reduced the synergism in these models. PI3K/Akt activation was synergistically induced by treatment of those isoflavones simultaneously. In summary, cav-1 could be a potential therapeutic target for protecting the BBB in the treatment of cerebral I/R injury. Major findings in this thesis include: 1) Cav-1 plays an important role in maintaining BBB integrity through inhibition of MMPs activity. NO induced MMPs activities and BBB leakage are partially mediated by the down-regulation of cav-1 during cerebral I/R injury. 2) Calycosin treatment reserved cav-1 expression and reduced BBB permeability. 3) Isoflavones synergistically protected neurons against I/R-induced neuronal insults both in vitro and in vivo. The works provide a valuable step towards the clarification of the physiological and pathophysiological functions of cav-1, and a new clue for developing isoflavones as agents targeting cav-1 for the prevention or treatment of ischemic stroke.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshMembrane proteins-
dc.subject.lcshCerebrovascular disease - Treatment-
dc.subject.lcshIsoflavones-
dc.titleTargeting caveolin-1 as a therapeutic approach to prevent blood-brain barrier breakdown in ischemic stroke : from mechanism to isoflavones treatment-
dc.typePG_Thesis-
dc.identifier.hkulb5194788-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineChinese Medicine-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5194788-

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