RT Journal Article
SR Electronic
T1 Remediation of Hemorrhagic Shock-Induced Intestinal Barrier Dysfunction by Treatment with Diphenyldihaloketones EF24 and CLEFMA
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 413
OP 422
DO 10.1124/jpet.114.217331
VO 351
IS 2
A1 Vivek R. Yadav
A1 Alamdar Hussain
A1 Kaustuv Sahoo
A1 Vibhudutta Awasthi
YR 2014
UL http://jpet.aspetjournals.org/content/351/2/413.abstract
AB Gut is very sensitive to hypoperfusion and hypoxia, and deranged gastrointestinal barrier is implicated in systemic failure of various organs. We recently demonstrated that diphenyldihaloketone EF24 [3,5-bis(2-fluorobenzylidene)piperidin-4-one] improves survival in a rat model of hemorrhagic shock. In this study, we tested EF24 and its other analog CLEFMA (4-[3,5-bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl]-4-oxo-2-butenoic acid) for their effect on intestinal barrier dysfunction in hypovolemic shock. Hypovolemia was induced in rats by withdrawing 50% of blood. EF24 or CLEFMA (0.4 mg/kg i.p.) treatment was provided, without volume resuscitation, after 1 hour of hemorrhage. Ileum was collected 5 hours after the treatment to investigate the expression of tight junction proteins (zonula occludens, claudin, and occludin) and epithelial injury markers [myeloperoxidase, ileal lipid-binding protein (ILBP), CD163, and plasma citrulline]. The ileal permeability for dextran-fluoroisothiocyanate and Evan’s blue dye was determined. EF24 and CLEFMA reduced the hypovolemia-induced plasma citrulline levels and the ileal expression of myeloperoxidase, ILBP, and CD163. The drugs also restored the basal expression levels of zonula occludens, claudin, and occludin, which were substantially deranged by hypovolemia. In ischemic ileum, the expression of phospho(tyrosine)-zonula occludens-1 was reduced, which was reinstated by EF24 and CLEFMA. In contrast, the drug treatments maintained the hypovolemia-induced expression of phospho(threonine)-occludin, but reduced that of phospho(tyrosine)-occludin. Both EF24 and CLEFMA treatments reduced the intestinal permeability enhanced by hypovolemia. EF24 and CLEFMA attenuate hypovolemic gut pathology and protect barrier function by restoring the status of tight junction proteins. These effects were observed in unresuscitated shock, implying the benefit of EF24 and CLEFMA in prehospital care of shock.