Interaction of Estrogen and Tissue Plasminogen Activator

雌激素和组织纤溶酶原激活剂的相互作用

基本信息

批准号：
7371350
负责人：
SHAOHUA YANG
金额：
$ 25.2万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-15 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7371350
关键词：
Acute Address Adverse effects Alteplase Astrocytes Attenuated Blood - brain barrier anatomy Cerebral Ischemia Cerebrum Clinical Trials Combination Drug Therapy Combined Modality Therapy Estradiol Estrogens Etiology European Female Fibrinolysis Gelatinase A Gelatinase B Glutamates Hemorrhage Hour Inhibition of Matrix Metalloproteinases Pathway Institutes Intervention Investigation Ischemic Stroke MMP2 gene MMP9 gene Matrix Metalloproteinases Middle Cerebral Artery Occlusion Modeling Morbidity - disease rate N-Methylaspartate Neurodegenerative Disorders Neurologic Neurons Neuroprotective Agents Pathogenesis Patients Personal Satisfaction Plasminogen Activator Plasminogen Inactivators Property Rate Rattus Recurrence Regulation Reperfusion Injury Risk Role Stroke Testing Therapeutic Therapeutic Intervention Time Toxic effect Yang acute stroke artery occlusion cell injury clinical application improved male middle cerebral artery mortality nervous system disorder neuroprotection neurotoxicity prevent research study thrombolysis

项目摘要

DESCRIPTION (provided by applicant): The demonstration that recombinant tissue plasminogen activator (rtPA) is useful for acute management is changing the approach to ischemic stroke. However, after more than a decade, the use of tPA therapy remains limited. Several factors could contribute to this limitation: irreversible cell damage induced by cerebral ischemia over time; the profile of rtPA treated patients at high risk of hemorrhagic transformation; and the potential detrimental effects of rtPA. Combination pharmacotherapy strategies to expand the rtPA fibrinolysis time window beyond 3 hours are under active investigation. In principle, it may be possible to extend the therapeutic window for rtPA therapy by using a neuroprotective drug. Estrogen is well known to diminish the neurotoxicity caused by NMDA activation. Preliminary evidence is presented in this proposal showing that 17¿-estradiol stabilizes blood brain barriers (BBB) against cerebral ischemia reperfusion injury through inhibition of matrix metalloproteinase 2 and 9 (MMP2, MMP9) activation, the major factors related to hemorrhagic transformation. 17¿-estradiol attenuates rtPA induced MMP2 and MMP9 activation in primary astrocytes. Most importantly, we have demonstrated that 17¿-estradiol extends the therapeutic window of rtPA upon pretreatment in female rats in an embolic middle cerebral artery occlusion (MCAO) model. Thus, the protective properties of estrogen make it a good candidate for combination therapy with rtPA. The neuroprotective effects of estrogen could delay irreversible cell damage. Further, estrogen may attenuate the side effects of rtPA, thereby prolonging the therapeutic window of rtPA and greatly broaden its clinical application. The present application will test the hypothesis that 17¿-estradiol extends therapeutic window of rtPA in embolic stroke, and determine the underlain mechanisms. To achieve these objectives, the following specific aims will be addressed. 1) To assess the interaction of estrogen and rtPA on glutamate neurotoxicity and matrix metalloproteinases (MMPs) activation. 2) To determine if 17¿-estradiol extend the therapeutic window of rtPA in female rats in an embolic stroke model. 3) To determine if 17¿-estradiol extend the therapeutic window of rtPA in male rats in an embolic stroke model. The application's objectives are to explore the feasibility for further clinical trials of combination therapy of estrogen and rtPA for ischemic stroke.The demonstration that recombinant tissue plasminogen activator (rtPA) is useful for acute management is changing the approach to ischemic stroke. However, after more than a decade, the use of rtPA therapy remains limited and has had only a modest impact in the overall burden of ischemic stroke. Several factors could contribute to this limitation: irreversible cell damage induced by cerebral ischemia over time; the profile of rtPA treated patients at high risk of hemorrhage; and the potential side effects of rtPA. Combination pharmacotherapy strategies to expand the 3 hour therapeutic window rtPA are under active investigation. In principle, it may be possible to extend the therapeutic window for rtPA therapy by using a neuroprotective drug. Preliminary evidence is presented in this proposal showing that estrogen can protect against ischemic stroke, and potentially attenuate side effect of rtPA. The present application will test the hypothesis that 17¿-estradiol extends therapeutic window of rtPA in embolic stroke, and determine the underlain mechanisms. The application's objectives are to explore the feasibility for further clinical trials of combination therapy of estrogen and rtPA for ischemic stroke.

描述（由申请人提供）：重组组织纤溶酶原激活剂（RTPA）对急性管理有用的证明正在改变缺血性中风的方法。但是，经过十多年的使用，使用TPA疗法仍然有限。几个因素可能导致这种限制：随着时间的流逝，脑缺血引起的不可逆细胞损伤； RTPA的特征治疗了出血转化的高风险的患者；以及RTPA的潜在有害影响。将RTPA纤维蛋白溶解时间窗口扩展到3小时以上的组合药理学策略正在积极投资。原则上，可以使用神经保护药物扩展RTPA治疗的治疗窗口。众所周知，雌激素会减少由NMDA激活引起的神经毒性。该提案中提供了初步证据，表明17？ - 雌二醇通过抑制基质金属蛋白酶2和9（MMP2，MMP9）激活而稳定血液脑屏障（BBB）针对脑缺血再灌注损伤，与出血转化有关的主要因素。 17�-雌二醇减弱RTPA在原代星形胶质细胞中诱导的MMP2和MMP9激活。最重要的是，我们已经证明17？ - 雌二醇在栓塞性大鼠栓塞中大鼠（MCAO）模型中预处理时扩展了RTPA的治疗窗口。这，雌激素的保护特性使其成为与RTPA联合疗法的良好候选者。雌激素的神经保护作用可能会延迟不可逆的细胞损伤。此外，雌激素可能会衰减RTPA的副作用，从而延长RTPA的治疗窗口并大大扩大其临床应用。本应用将检验以下假设：17？ - 雌二醇在栓塞中延伸RTPA的热窗口，并确定下层机理。为了实现这些目标，将解决以下特定目标。 1）评估雌激素和RTPA在谷氨酸神经毒性和基质金属蛋白酶（MMP）激活上的相互作用。 2）确定在栓塞模型中，雌性大鼠中RTPA的治疗窗口是否扩展了17？雌二醇。 3）确定在栓塞模型中，雄性大鼠中RTPA的治疗窗口是否扩展了17？雌二醇。该应用程序的目标是探索雌激素和RTPA组合治疗的进一步临床试验的可行性。重组组织纤溶酶原激活剂（RTPA）对急性管理有用的证明正在改变缺血性中风的方法。但是，经过十多年的使用，RTPA疗法的使用仍然有限，并且对缺血性中风的整体燃烧只有适度的影响。几个因素可能导致这种限制：随着时间的流逝，脑缺血引起的不可逆细胞损伤； RTPA的特征治疗了高出血风险的患者； RTPA的潜在副作用。扩大3小时治疗窗口RTPA的组合药物治疗策略正在积极投资。原则上，可以使用神经保护药物扩展RTPA治疗的治疗窗口。该提案中提供了初步证据，表明雌激素可以预防缺血性中风，并可能减弱RTPA的副作用。本应用将检验以下假设：17？ - 雌二醇在栓塞中延伸RTPA的热窗口，并确定基础机理。该应用程序的目标是探索雌激素和RTPA组合治疗的进一步临床试验的可行性。