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；

• 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
• 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' 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' 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

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.

几乎三分之二的中风幸存者表现出血管认知障碍，三分之一的中风患者会在中风后1-3年患上痴呆症。更年期显著增加了中风的风险，并可能是女性AD/ADRD患病率高于男性的原因。使用无周期的中年雌性大鼠来模拟雌激素缺乏的绝经后状态，我们发现与正常周期的成年雌性大鼠相比，缺血性中风在这一群体中产生了更大的脑梗塞，而矛盾的是，雌激素治疗增加了老年无周期雌性大鼠的脑损伤。这些数据与妇女健康倡议研究一致，在该研究中，接受激素治疗的妇女中风风险和死亡率增加，并强调了为这一老年人口群体寻找新的治疗方法的必要性。 我们以前的工作表明，多肽激素胰岛素样生长因子-1(Insulin-like Growth Factor，IGF-1)可在卒中后将多肽激素胰岛素样生长因子-1(Insulin-like Growth Factor-1，IGF-1)送入无循环中年雌性大鼠的脑室(Icv)，减少梗塞体积和神经炎症，并在急性期保护血脑屏障功能。由于中风会导致长期的痴呆症相关症状，如抑郁和认知障碍，我们启动了关于这些结果的初步研究。令人惊讶的是，ICV-IGF-1在中风后30-60天测量时并未改善抑郁行为，也未能降低急性或慢性期血清中炎性细胞因子的水平。 我们认为，ICV-IGF-1在急性期具有强大的神经保护作用与对慢性卒中预后缺乏影响之间的二分法，是因为ICV-IGF-1不适用于对抑制炎症和长期卒中恢复至关重要的脑外靶器官。 有证据表明，肠道是免疫细胞数量最多的地方，而肠道代谢产物，如短链脂肪酸，对于减少外周炎症和改善血脑屏障完整性至关重要，我们认为，改善中风的长期结果将需要IGF-1对肠道屏障起作用。肠道屏障对于抑制免疫反应和减少肠道生物失调至关重要。在这里，我们将测试与ICV-IGF-1相比，外周IGF-1(ip或口服)将改善(A)急性中风残疾(2-5d)以及慢性期(21-180d)的抑郁样行为和认知障碍，(B)保护肠道屏障，从而防止激活的肠道免疫细胞外溢，以及(C)改善肠道微生物区系和肠道代谢物的慢性促炎变化。 这些研究在评估中风的长期认知影响方面是创新的，而在临床前研究中，这些研究还没有得到充分的研究。此外，我们对生殖衰老雌性大鼠的关注反映了人类绝经后女性的老龄化，具有独特的翻译相关性，因为AD/ADRD在雌性中的患病率要高得多。在这些研究的结论中，我们期望对额外的神经靶点在调节中风后痴呆中的作用有更好的理解。