Targeting the gut for stroke neuroprotection; IGF-1 modulation of the blood-gut barrier

针对中风神经保护的肠道；

基本信息

批准号：
10366982
负责人：
Shameena Bake
金额：
$ 169.58万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366982
关键词：
16S ribosomal RNA sequencing Acute Adult Aftercare Aging Alzheimer&apos s disease related dementia Animal Model Animals Architecture Behavior Blood Blood - brain barrier anatomy Blood Circulation Blood Preservation Brain Brain Infarction Brain Injuries Cells Cerebrovascular Disorders Chronic Chronic Phase Cognitive Complex Data Dementia Dextrans Disease Encapsulated Epithelial Attachment Epithelial Cells Estrogen Therapy Estrogens Exhibits Extravasation Feces Female Geometry Gut associated lymphoid tissue Home Hormones Human Immune Immune response Impaired cognition Impairment Incidence Infarction Inflammation Inflammation Mediators Inflammatory Influentials Insulin-Like Growth Factor I Insulin-Like Growth Factor Receptor Intestinal permeability Ischemic Stroke Label Leukocytes Link Matrix Metalloproteinases Measures Mediating Mediator of activation protein Memory Menopause Mental Depression Middle Cerebral Artery Occlusion Modeling Motor Myocardial Infarction Neurologic Oral Organ Outcome Pathology Performance Peripheral Phase Pilot Projects Population Positioning Attribute Postmenopause Prevalence Prostaglandins Quality of life Rattus Recurrence Regimen Reporting Risk Risk Factors Role Sensory Serum Severity of illness Small Intestines Social Interaction Somatomedins Stroke Symptoms System Testing Time Tryptophan Vascular Cognitive Impairment Villus Volatile Fatty Acids Woman Women&apos s Health Work acute stroke age related blood-brain barrier function blood-brain barrier permeabilization brain health brain tissue cardiovascular disorder risk chronic stroke cytokine depressive behavior depressive symptoms disability disorder risk experience experimental study fecal microbiome gut dysbiosis gut microbes gut microbiome gut microbiota health management hormone therapy improved innovation intestinal barrier intestinal epithelium intraperitoneal men microbial middle age mortality motor impairment neurobehavioral neuroinflammation neuroprotection neuropsychiatry neurotoxic novel therapeutic intervention older women peptide hormone post stroke post stroke dementia pre-clinical pre-clinical research preclinical study preservation prevent relating to nervous system repaired reproductive senescence stroke outcome stroke patient stroke recovery stroke risk stroke survivor stroke therapy

项目摘要

Almost 2/3rds of stroke survivors exhibit vascular cognitive impairment and a third of stroke patients will develop dementia 1-3 years after stroke. Menopause significantly increases the risk for stroke and may underlie the greater prevalence of AD/ADRD seen in women as compared to men. Using acyclic middle-aged female rats to model the estrogen-deficient postmenopausal state, we found that ischemic stroke produced larger brain infarcts in this population as compared to normally-cycling, adult females, and that estrogen treatment, paradoxically, increased brain damage in older acyclic female rats. These data are congruent with the Women’s Health Initiative study, where the stroke risk and mortality were elevated in women who received hormone therapy and underscores the need for novel therapeutic approaches for this older demographic. Our previous work shows that the peptide hormone Insulin-like Growth Factor (IGF)-1 delivered intracerebroventricularly (icv) to acyclic middle-aged female rats after stroke, reduces infarct volume and neuroinflammation, and preserves blood brain barrier function during the acute phase. Since stroke leads to long term dementia-related symptoms such as depression and cognitive impairment, we initiated pilot studies on these outcomes. Surprisingly, icv-IGF-1 did not improve depressive behaviors when measured 30-60 days after stroke and failed to reduce serum levels of inflammatory cytokines either in the acute or chronic phase. We propose that the dichotomy between the robust neuroprotective actions of icv-IGF-1 in the acute phase, with the lack of effect on chronic stroke outcomes occurs because icv-IGF-1 is not available to target organs outside the brain that are critical for suppressing inflammation and long-term stroke recovery. In view of the evidence that the gut is home to the largest contingent of immune cells, and gut metabolites such as short chain fatty acids are critical for reducing peripheral inflammation and improving blood brain barrier integrity, we propose that improvement of long-term outcomes from stroke will require IGF-1 action on the gut intestinal barrier. The intestinal barrier is critical for containing the immune response and reducing gut dysbiosis. Here we will test the hypothesis that in contrast to icv-IGF-1, peripheral IGF-1 (ip or oral), will improve (a) acute stroke disability (2-5d) as well as depressive-like behaviors and cognitive impairment in the chronic phase (21-180d), (b) preserve the intestinal barrier, thus preventing the extravasation of activated gut immune cells and (c) ameliorate chronic pro-inflammatory changes to the gut microbiota and gut metabolites. These studies are innovative in assessing the long-term cognitive effects of stroke which are understudied in preclinical research. In addition, our focus on reproductive senescent female rats that is reflective of the aging human post-menopausal female, has unique translational relevance, since the prevalence of AD/ADRD is much higher in females. At the conclusion of these studies, we expect to have a better understanding of the role of extra neural targets in mediating post-stroke dementia.

近2/3的中风存活暴露的血管认知障碍和中风患者中有三分之一将在中风后1 - 3年发展痴呆。更年期大大增加了中风的风险，与男性相比，女性中观察到的AD/ADRD的患病率更高。使用无环中年雌性大鼠对绝经后状态进行建模，我们发现，与正常的伴侣，成年女性相比，缺血性中风会在该人群中产生较大的脑部，并且雌激素治疗（矛盾的是）在老年雌性大鼠中会增加大脑损伤。这些数据与妇女的健康倡议研究是一致的，在接受马酮治疗并强调对这种较旧的人群的新型治疗方法的需求的女性中，中风风险和死亡率升高。我们以前的工作表明，辣椒胰岛素样生长因子（IGF）-1在中风后将脑室内室内（ICV）递送到异步中年雌性大鼠，可减少梗塞体积和神经炎症，并保留急性阶段期间的血液脑屏障功能。由于中风会导致长期与痴呆相关的症状，例如抑郁和认知障碍，因此我们就这些结果开始了试点研究。令人惊讶的是，ICV-IGF-1在中风后30-60天测量时，ICV-IGF-1并不能改善抑郁行为，并且在急性或慢性期未能降低炎症细胞因子的血清水平。我们建议，ICV-IGF-1在急性阶段的稳健神经保护作用之间的二分法，由于ICV-IGF-1对抑制注射和长期的中风恢复至关重要的目标器官不可用，因此缺乏对慢性中风结果的影响。鉴于肠道是最大的免疫细胞特征的证据，而肠道代谢产物（例如短链脂肪酸）对于减少外周种感染和改善血脑屏障的完整性至关重要，我们建议改善卒中长期结局将需要对肠道上的肠道肠道壁垒进行IGF-1作用。肠屏障对于含有免疫激发和减少肠道营养不良至关重要。 Here we will test the hypothesis that in contrast to icv-IGF-1, peripheral IGF-1 (ip or oral), will improve (a) acute stroke disability (2-5d) as well as depressive-like behaviors and cognitive impairment in the chronic phase (21-180d), (b) preserve the intestinal barrier, thus preventing the extravasation of activated gut immunocells and (c)改善肠道菌群和肠道代谢产物的慢性促炎性变化。这些研究在评估临床前研究中理解的中风的长期认知作用方面具有创新性。此外，我们对反映人类衰老后女性女性的生殖敏感性的雌性大鼠具有独特的翻译相关性，因为AD/ADRD的患病率在女性中要高得多。在这些研究结束时，我们希望更好地了解额外的神经靶标在中风后痴呆症中的作用。