beta-escin and Intestinal-Diseases

Hyperactivity of HPA axis results in intestinal dysfunction, which may play a role in brain injury caused by ischemic stroke (IS). Escin shows a neuroprotective effect but it may not penetrate blood brain barrier (BBB). Previous work in our laboratory showed that escin ameliorated intestinal injury in animals. The aim of this study is to investigate whether escin attenuates brain injury by improving intestinal dysfunction in middle cerebral artery occlusion (MCAO) rats, to mimic IS. MCAO rats and lipopolysaccharides (LPS)-induced Caco-2 cells were used to evaluate the effects of escin in vivo and in vitro. The results showed that escin could not penetrate BBB but reduced brain infarct volume, improved neurological function, inhibited neuroinflammation, ameliorated intestinal dysfunction and tissue integrity by increasing the expression of the tight junction protein in vivo and in vitro. Escin reduced the increased corticosterone and endotoxin level in blood of MCAO rats, regulated GR/p38 MAPK/NF-κB signaling pathway in ileal tissue and LPS/TLR4/NF-κB signaling pathway in ischemic brain tissue. These findings suggest that escin could attenuate ischemic brain injury by improving intestinal dysfunction, and it may be a promising way to protect brain injury by protecting intestine, instead of targeting the brain directly after IS.

Topics: Animals; Brain Injuries; Brain Ischemia; Brain-Gut Axis; Caco-2 Cells; Escin; Gastrointestinal Diseases; Humans; Hypothalamo-Hypophyseal System; Infarction, Middle Cerebral Artery; Intestinal Diseases; Ischemic Stroke; Lipopolysaccharides; NF-kappa B; Pituitary-Adrenal System; Rats; Reperfusion Injury; Stroke

Motility disorders are frequently observed in intestinal inflammation. We previously reported that in vitro treatment of intestinal smooth muscle tissue with IL-1beta decreases the expression of CPI-17, an endogenous inhibitory protein of smooth muscle serine/threonine protein phosphatase, thereby inhibiting contraction. The present study was performed to examine the pathophysiological importance of CPI-17 expression in the motility disorders by using an in vivo model of intestinal inflammation and to define the regulatory mechanism of CPI-17 expression by proinflammatory cytokines. After the induction of acute ileitis with 2,4,6,-trinitrobenzensulfonic acid, CPI-17 expression declined in a time-dependent manner. This decrease in CPI-17 expression was parallel with the reduction of cholinergic agonist-induced contraction of smooth muscle strips and sensitivity of permeabilized smooth muscle fibers to Ca(2+). Among the various proinflammatory cytokines tested, TNF-alpha and IL-1beta were observed to directly inhibit CPI-17 expression and contraction in cultured rat intestinal tissue. Moreover, both TNF-alpha and IL-1beta inhibited CPI-17 expression and contraction of smooth muscle tissue isolated from wild-type and IL-1alpha/beta double-knockout mice. However, IL-1beta treatment failed to inhibit CPI-17 expression and contraction in TNF-alpha knockout mice. In beta-escin-permeabilized ileal tissues, pretreatment with anti-phosphorylated CPI-17 antibody inhibited the carbachol-induced Ca(2+) sensitization in the presence of GTP. These findings suggest that CPI-17 was downregulated during intestinal inflammation and that TNF-alpha plays a central role in this process. Downregulation of CPI-17 may play a role in motility impairments in inflammation.

Topics: Animals; Carbachol; Disease Models, Animal; Down-Regulation; Escin; Gastrointestinal Motility; Ileitis; Interleukin-1beta; Intestinal Diseases; Intracellular Signaling Peptides and Proteins; Male; Mice; Muscle Proteins; Muscle, Smooth; Phosphoproteins; Rats; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha