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

几乎三分之二的中风幸存者表现出血管性认知障碍，三分之一的中风患者将在中风后1-3年发展为痴呆。绝经显著增加了中风的风险，可能是女性AD/ADRD患病率高于男性的原因。使用非周期性中年雌性大鼠模型雌激素缺乏的绝经后状态，我们发现，缺血性中风产生较大的脑梗死，在这个人口相比，正常的周期性，成年女性，和雌激素治疗，矛盾的是，增加脑损伤的老年非周期性雌性大鼠。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升高，并强调了对这种老年人口的新治疗方法的需求。 我们以前的工作表明，脑室内（icv）注射胰岛素样生长因子（IGF）-1肽激素给无周期中年雌性大鼠脑卒中后，减少梗死体积和神经炎症，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相关症状，如抑郁和认知障碍，我们开始了对这些结果的初步研究。令人惊讶的是，在中风后30-60天测量时，icv-IGF-1并没有改善抑郁行为，并且在急性或慢性阶段都没有降低炎性细胞因子的血清水平。 我们提出，icv-IGF-1在急性期的强大神经保护作用与对慢性卒中结局缺乏影响之间的二分法发生，因为icv-IGF-1不能用于脑外的靶器官，这些器官对于抑制炎症和长期卒中恢复至关重要。 有证据表明，肠道是最大的免疫细胞队伍的家园，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，我们建议改善中风的长期结局将需要IGF-1对肠道屏障的作用。肠道屏障对于抑制免疫反应和减少肠道生态失调至关重要。在这里，我们将测试与icv-IGF-1相反，外周IGF-1（ip或口服），将改善（a）急性中风残疾（2- 5天）以及慢性期（21- 180天）的抑郁样行为和认知障碍，（B）保护肠屏障，从而防止激活的肠道免疫细胞的外渗，和（c）改善肠道微生物群和肠道代谢物的慢性促炎性变化。 这些研究在评估中风的长期认知影响方面具有创新性，这些影响在临床前研究中未得到充分研究。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衰老，具有独特的翻译相关性，因为AD/ADRD在女性中的患病率要高得多。在这些研究的结论，我们希望有一个更好的了解额外的神经靶点在介导中风后痴呆症的作用。

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.