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Multiple mechanisms of TRPV1-mediated brain protection following stroke

TRPV1介导的中风后脑保护的多种机制

基本信息

批准号：
9551722
负责人：
Sean P Marrelli
金额：
$ 23.78万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9551722
关键词：
Adjuvant Adult Affect Agonist Area Blood - brain barrier anatomy Blood Vessels Blood flow Body Temperature Brain Brain Injuries Brain region Capsaicin Cause of Death Cerebrovascular Circulation Cerebrum Chemosensitization Conscious Contralateral Data Defense Mechanisms Doppler Echocardiography Dose Endothelium Evaluation Health Hemorrhage Histology Immunofluorescence Immunologic Ipsilateral Ischemia Knock-out Knockout Mice Lasers Lead Measurement Measures Mediating Methods Modeling Modification Mus Oxidants Oxidative Stress Perfusion Pharmacology Phase Preparation Reactive Oxygen Species Reducing Agents Reperfusion Therapy Role Stroke System TRPV1 gene Temperature Testing Therapeutic Transgenic Mice Transgenic Organisms Vanilloid Vasodilation aged arm behavior test cerebral artery cerebral microvasculature cerebrovascular disability experimental study hypoperfusion improved in vivo induced hypothermia injured middle cerebral artery natural hypothermia neuroprotection novel pressure protective effect receptor response restoration sex stroke treatment tool

项目摘要

Stroke is a significant health problem with limited treatment options. In this application, we present a new model in which activation of transient receptor potential vanilloid 1 (TRPV1) channels provides neuroprotection following ischemia/reperfusion (I/R) through two independent yet additive mechanisms. First, we provide evidence that pharmacological activation of vascular TRPV1 channels during the reperfusion phase selectively restores cerebral perfusion to the damaged brain regions. The hypoperfusion which occurs in damaged brain during early reperfusion can be dramatically and quickly restored without affecting the flow in non-injured brain regions. We propose that reactive oxygen species (ROS) produced following stroke lead to increased TRPV1 channel sensitivity to agonists, and thus the increased cerebral blood flow response. Second, activation of TRPV1 channels in the thermoregulatory system produces a rapid and sustainable decrease in body temperature (mild hypothermia) that is neuroprotective. In this context, TRPV1 activation effectively lowers the body's temperature “set point”, allowing for a more rapid and controlled level of therapeutic hypothermia to be achieved. We have already established that pharmacological activation of TRPV1 channels (“TRPV1 agonism”) is neuroprotective. While part of the neuroprotective effect is through induction of mild hypothermia, our new studies indicate that an additional protective effect may be through restoration of flow to hypoperfused brain regions. We now propose the overall hypothesis that TRPV1 agonism provides two arms of protection following stroke by 1) improving reperfusion in injured brain regions and 2) promoting protective hypothermia. We will study these mechanisms separately and then in combination to determine the additive benefit following stroke in adult and aged mice of both sexes. In aim 1, we will demonstrate selective increase in cerebral blood flow within the ischemia/reperfusion territory with TRPV1 agonism. These studies include in vivo cerebral blood flow measurements in adult and aged mice of both sexes following stroke. In aim 2, we will determine the role of ROS in potentiating endothelial TRPV1- mediated vasodilation and increased cerebral blood flow using isolated cerebral arteries and in vivo preparations. We will use a combination of pharmacological approaches, available knockout/transgenic mice, and a novel knockout mouse to demonstrate the specific role of endothelial TRPV1 channels and NOX-derived ROS in the mechanism. In aim 3, we will demonstrate the long-term neuroprotective benefit of TRPV1 agonism following stroke. We will evaluate the vascular component alone (hypothermia-independent mechanism) as well as the combined vascular and hypothermic components (hypothermia-dependent mechanism). Aged mice of both sexes will be evaluated by behavioral testing, histology, and blood brain barrier function during the course of one month of reperfusion. All together, these studies should establish TRPV1 agonism as a multi-faceted approach to neuroprotection following stroke.

中风是一种严重的健康问题，治疗方法有限。在这个应用中，我们提出了一个新的模型