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在中风后1-3年将发展为痴呆。更年期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。使用无循环中年雌性大鼠来模拟绝经后雌激素缺乏的状态，我们发现，与正常循环的成年雌性相比，缺血性中风在这一人群中产生了更大的脑梗死，而雌激素治疗反而增加了老年无循环雌性大鼠的脑损伤。这些数据与妇女健康倡议研究一致，接受激素治疗的妇女中风风险和死亡率升高，并强调了对老年人口的新治疗方法的需求。

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.