Altered occludin expression in brain capillaries induced by obstructive jaundice in rats

Faropoulos, Konstantinos; Chroni, Elisabeth; Assimakopoulos, Stelios F.; Mavrakis, Adamantios; Stamatopoulou, Vassiliki; Toumpeki, Chrisavgi; Drainas, Denis; Grintzalis, Konstantinos; Papapostolou, Ioannis; Georgiou, Christos D.; Konstantinou, Dimitrios

doi:10.1016/j.brainres.2010.02.020

Cited by 25 publications

(19 citation statements)

References 39 publications

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“…Several reports have shown that BDL affects neither BBB integrity [42] nor the www.nature.com/aps Xu P et al Acta Pharmacologica Sinica expression of occludin and claudin-5 in the brains of rats [43] , which is consistent with our findings. However, Faropoulos et al have reported that BDL time-dependently down-regulates occludin expression in the brains of rats [35] . Another study has demonstrated that BDL impairs the BBB integrity of rats, as evidenced by increased brain extravasation of Evans Blue [44] .…”

Section: Discussionmentioning

confidence: 97%

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Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats

Ling

Zhang

et al. 2016

Acta Pharmacol Sin

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Aim: Liver failure is associated with dyshomeostasis of efflux transporters at the blood-brain barrier (BBB), which contributes to hepatic encephalopathy. In this study we examined whether breast cancer resistance protein (BCRP), a major efflux transporter at the BBB, was altered during liver failure in rats. Methods: Rats underwent bile duct ligation (BDL) surgery, and then were sacrificed after intravenous injection of prazosin on d3, d7 and d14. The brains and blood samples were collected. BCRP function at the BBB was assessed by the brain-to-plasma prazosin concentration ratio; Evans Blue extravasation in the brain tissues was used as an indicator of BBB integrity. The protein levels of BCRP in the brain tissues were detected. Human cerebral microvessel endothelial cells (HCMEC/D3) and Madin-Darby canine kidney cells expressing human BCRP (MDCK-BCRP) were tested in vitro. In addition, hyperbilirubinemia (HB) was induced in rats by intravenous injection of unconjugated bilirubin (UCB). Results: BDL rats exhibited progressive decline of liver function and HB from d3 to d14. In the brain tissues of BDL rats, both the function and protein levels of BCRP were progressively decreased, whereas the BBB integrity was intact. Furthermore, BDL rat serum significantly decreased BCRP function and protein levels in HCMEC/D3 cells. Among the abnormally altered components in BDL rat serum tested, UCB (10, 25 µmol/L) dose-dependently inhibit BCRP function and protein levels in HCMEC/D3 cells, whereas 3 bile acids (CDCA, UDCA and DCA) had no effect. Similar results were obtained in MDCK-BCRP cells and in the brains of HB rats. Correlation analysis revealed that UCB levels were negatively correlated with BCRP expression in the brain tissues of BDL rats and HB rats as well as in two types of cells tested in vitro. Conclusion: UCB elevation in BDL rats impairs the function and expression of BCRP at the BBB, thus contributing to hepatic encephalopathy.

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Section: Discussionmentioning

confidence: 97%

“…Development of BDL rats BDL rats were induced according to a previously described method [24,34,35] . Briefly, rats were anesthetized via an injection of pentobarbitone (40 mg/kg, ip).…”

Section: Animalsmentioning

confidence: 99%

Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats

Ling

Zhang

et al. 2016

Acta Pharmacol Sin

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“…These proinflammatory cytokines progress in parallel with the severity of astrocyte swelling [46]. The alterations in blood-brain barrier remain unclear although some studies have shown disruption of tight junction proteins indicative of involvement of blood-brain barrier in cellular swelling [48,49]. Hypertrophy of end-feet of astrocytes was evident after BDL surgery, but there was no noticeable difference between the BDL and BDLHD rats.…”

Section: Discussionmentioning

confidence: 99%

Morphological changes of cortical pyramidal neurons in hepatic encephalopathy

et al. 2014

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BackgroundHepatic encephalopathy (HE) is a reversible neuropsychiatric syndrome associated with acute and chronic liver diseases. It includes a number of neuropsychiatric disturbances including impaired motor activity and coordination, intellectual and cognitive function.ResultsIn the present study, we used a chronic rat HE model by ligation of the bile duct (BDL) for 4 weeks. These rats showed increased plasma ammonia level, bile duct hyperplasia and impaired spatial learning memory and motor coordination when tested with Rota-rod and Morris water maze tests, respectively. By immunohistochemistry, the cerebral cortex showed swelling of astrocytes and microglia activation. To gain a better understanding of the effect of HE on the brain, the dendritic arbors of layer V cortical pyramidal neurons and hippocampal CA1 pyramidal neurons were revealed by an intracellular dye injection combined with a 3-dimensional reconstruction. Although the dendritic arbors remained unaltered, the dendritic spine density on these neurons was significantly reduced. It was suggested that the reduction of dendritic spines may be the underlying cause for increased motor evoked potential threshold and prolonged central motor conduction time in clinical finding in cirrhosis.ConclusionsWe found that HE perturbs CNS functions by altering the dendritic morphology of cortical and hippocampal pyramidal neurons, which may be the underlying cause for the motor and intellectual impairments associated with HE patients.

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“…However, instead of affecting hepatic glucocorticoid clearance (37), we hypothesize that the bile acids may enter the brain and suppress the HPA axis directly. Others have shown that the blood-brain barrier becomes leaky in rodent models of cholestasis (12,56), allowing access of aberrant signaling molecules to the brain. We have preliminary data to suggest that there are increased amounts of bile acids in the brain after BDL and that these bile acids have a dampening effect on the HPA axis (DeMorrow et al, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Suppression of the HPA axis during extrahepatic biliary obstruction induces cholangiocyte proliferation in the rat

Quinn¹,

Ueno

Pae

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Cholestatic patients often present with clinical features suggestive of adrenal insufficiency. In the bile duct-ligated (BDL) model of cholestasis, the hypothalamic-pituitaryadrenal (HPA) axis is suppressed. The consequences of this suppression on cholangiocyte proliferation are unknown. We evaluated 1) HPA axis activity in various rat models of cholestasis and 2) effects of HPA axis modulation on cholangiocyte proliferation. Expression of regulatory molecules of the HPA axis was determined after BDL, partial BDL, and ␣-naphthylisothiocyanate (ANIT) intoxication. The HPA axis was suppressed by inhibition of hypothalamic corticotropinreleasing hormone (CRH) expression by central administration of CRH-specific Vivo-morpholinos or by adrenalectomy. After BDL, the HPA axis was reactivated by 1) central administration of CRH, 2) systemic ACTH treatment, or 3) treatment with cortisol or corticosterone for 7 days postsurgery. There was decreased expression of 1) hypothalamic CRH, 2) pituitary ACTH, and 3) key glucocorticoid synthesis enzymes in the adrenal glands. Serum corticosterone and cortisol remained low after BDL (but not partial BDL) compared with sham surgery and after 2 wk of ANIT feeding. Experimental suppression of the HPA axis increased cholangiocyte proliferation, shown by increased cytokeratin-19-and proliferating cell nuclear antigen-positive cholangiocytes. Conversely, restoration of HPA axis activity inhibited BDL-induced cholangiocyte proliferation. Suppression of the HPA axis is an early event following BDL and induces cholangiocyte proliferation. Knowledge of the role of the HPA axis during cholestasis may lead to development of innovative treatment paradigms for chronic liver disease.corticotropin-releasing hormone; glucocorticoids; biliary epithelium; adrenocorticotropic hormone CHOLANGIOCYTES ARE EPITHELIAL cells that line the intra-and extrahepatic bile ducts. They are constitutively mitotically dormant but possess marked proliferative capacity (2), which is apparent during experimental conditions, such as cholestasis induced by bile duct ligation (BDL) or ␣-naphthylisothiocyanate (ANIT) intoxication (1), as well as in human cholangiopathies (2). In humans, cholangiocyte proliferation occurs in extrahepatic biliary obstruction, in the course of chronic cholestatic liver diseases (e.g., primary sclerosing cholangitis, primary biliary cirrhosis, liver allograft rejection, and graft-vs.-host disease) (2), and in many forms of liver injury (e.g., in response to alcohol, toxin, or drugs) (2, 43).The hypothalamic-pituitary-adrenal (HPA) axis describes a complex set of positive-and negative-feedback influences between the hypothalamus, pituitary gland, and adrenal gland (25). These feedforward and feedback mechanisms work in a neuroendocrine manner to modulate a number of physiological processes, such as immunity (32), digestion (30), and the body's response to stress (30). In addition, the HPA axis has been shown to have an influence on human psychology (7, 53).The mechanism by which the HPA axis rem...

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Altered occludin expression in brain capillaries induced by obstructive jaundice in rats

Cited by 25 publications

References 39 publications

Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats

Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats

Morphological changes of cortical pyramidal neurons in hepatic encephalopathy

Suppression of the HPA axis during extrahepatic biliary obstruction induces cholangiocyte proliferation in the rat

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