scholarly journals TIMP-1 Attenuates Blood–Brain Barrier Permeability in Mice with Acute Liver Failure

2013 ◽  
Vol 33 (7) ◽  
pp. 1041-1049 ◽  
Author(s):  
Feng Chen ◽  
Evette S Radisky ◽  
Pritam Das ◽  
Jyotica Batra ◽  
Toshiyuki Hata ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Blood Brain Barrier ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Blood Brain ◽  
Junction Protein ◽  
Bbb Permeability

Blood-brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and D-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.

Functional impairment of blood-brain barrier following pesticide exposure during early development in rats

1999 ◽  
Vol 18 (3) ◽  
pp. 174-179 ◽  
Author(s):  
Alka Gupta ◽  
Renu Agarwal ◽  
Girja S Shukla
Keyword(s):  
Blood Brain Barrier ◽  
Repeated Exposure ◽  
Neurological Dysfunction ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Rat Pups ◽  
Blood Brain ◽  
Brain Uptake Index ◽  
Old Rats ◽  
Bbb Permeability

1 The effect of certain pesticides on the functional integrity of the developing blood-brain barrier (BBB) was studied following single and repeated exposure, and after subsequent withdrawal in rats. 2 Ten-day-old rat pups exposed orally to quinalphos (QP, organophosphate), cypermethrin (CM, pyre-throid) and lindane (LD, organochlorine) at a dose of 1/50th of LD50, showed a significant increase in the brain uptake index (BUI) for a micromolecular tracer, sodium fluorescein (SF), by 97, 37 and 72%, respectively, after 2 h. Residual increases in the BUI were found even after 3 days of the single treatment of QP (28%) and LD (23%). 3 Repeated exposure for 8 days (postnatal days (PND) 10-17) with QP, CM and LD increased the BBB permeability by 130, 80 and 50%, respectively. Recovery from these changes was complete in QP and LD-treated animals after 13 days (PND 18-30) of withdrawal. However, CM showed persistent effects that were normalized only after 43 days (PND 18-60) of withdrawal. 4 A single dose reduced to 1/100th of LD50 also increased BUI in 10-day-old rat pups following QP (20%) and CM (28%) exposure at 2 h. 5 An age-dependent effect of these pesticides was evident from the study showing higher magnitude of BUI changes in 10-day-old rats as compared to that in 15- day-old rats. Furthermore, adult rats did not show any effect on BBB permeability even at a higher dose (1/25th of LD50) of these pesticides given alone or in combination with piperonyl butoxide (600 mg/kg, i.p.) for 3 consecutive days. 6 This study showed that developing BBB is highly vulnerable to single or repeated exposure of certain pesticides. The observed persistent effects during brain development even after withdrawal of the treatment may produce some neurological dysfunction at later life as well.

scholarly journals Insight into microRNAs-Mediated Communication between Liver and Brain: A Possible Approach for Understanding Acute Liver Failure?

2021 ◽  
Vol 23 (1) ◽  
pp. 224
Author(s):  
Karolina Orzeł-Gajowik ◽  
Krzysztof Milewski ◽  
Magdalena Zielińska
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Blood Brain Barrier ◽  
Neuropsychiatric Symptoms ◽  
Hepatic Function ◽  
Brain Barrier ◽  
Circulating Mirnas ◽  
Blood Brain ◽  
Micro Rnas ◽  
Functional Components

Acute liver failure (ALF) is a life-threatening consequence of hepatic function rapid loss without preexisting liver disease. ALF may result in a spectrum of neuropsychiatric symptoms that encompasses cognitive impairment, coma, and often death, collectively defined as acute hepatic encephalopathy (HE). Micro RNAs are small non-coding RNAs that modulate gene expression and are extensively verified as biomarker candidates in various diseases. Our systematic literature review based on the last decade’s reports involving a total of 852 ALF patients, determined 205 altered circulating miRNAs, of which 25 miRNAs were altered in the blood, regardless of study design and methodology. Selected 25 miRNAs, emerging predominantly from the analyses of samples obtained from acetaminophen overdosed patients, represent the most promising biomarker candidates for a diagnostic panel for symptomatic ALF. We discussed the role of selected miRNAs in the context of tissue-specific origin and its possible regulatory role for molecular pathways involved in blood–brain barrier function. The defined several common pathways for 15 differently altered miRNAs were relevant to cellular community processes, indicating loss of intercellular, structural, and functional components, which may result in blood-brain barrier impairment and brain dysfunction. However, a causational relationship between circulating miRNAs differential expression, and particular clinical features of ALF, has to be demonstrated in a further study.

scholarly journals Increased blood–brain barrier permeability is not a primary determinant for lethality of West Nile virus infection in rodents

2008 ◽  
Vol 89 (2) ◽  
pp. 467-473 ◽  
Author(s):  
John D. Morrey ◽  
Aaron L. Olsen ◽  
Venkatraman Siddharthan ◽  
Neil E. Motter ◽  
Hong Wang ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Blood Brain Barrier ◽  
Semliki Forest Virus ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
West Nile ◽  
Blood Brain ◽  
Lethal Infection ◽  
Primary Determinant ◽  
Bbb Permeability

Blood–brain barrier (BBB) permeability was evaluated in mice and hamsters infected with West Nile virus (WNV, flavivirus) as compared to those infected with Semliki Forest (alphavirus) and Banzi (flavivirus) viruses. BBB permeability was determined by measurement of fluorescence in brain homogenates or cerebrospinal fluid (CSF) after intraperitoneal (i.p.) injection of sodium fluorescein, by macroscopic examination of brains after i.p. injection of Evans blue, or by measurement of total protein in CSF compared to serum. Lethal infection of BALB/c mice with Semliki Forest virus and Banzi virus caused the brain : serum fluorescence ratios to increase from a baseline of 2–4 % to as high as 11 and 15 %, respectively. Lethal infection of BALB/c mice with WNV did not increase BBB permeability. When C57BL/6 mice were used, BBB permeability was increased in some, but not all, of the WNV-infected animals. A procedure was developed to measure BBB permeability in live WNV-infected hamsters by comparing the fluorescence in the CSF, aspirated from the cisterna magnum, with the fluorescence in the serum. Despite a time-dependent tendency towards increased BBB permeability in some WNV-infected hamsters, the highest BBB permeability values did not correlate with mortality. These data indicated that a measurable increase in BBB permeability was not a primary determinant for lethality of WNV infection in rodents. The lack of a consistent increase in BBB permeability in WNV-infected rodents has implications for the understanding of viral entry, viral pathogenesis and accessibility of the CNS of rodents to drugs or effector molecules.

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