Discovery of pathway in learning impairment caused by liver disease may lead to drug treatment
Liver disease sometimes causes hepatic encephalopathy, which involves brain damage, personality changes, and intellectual impairment due to hyperammonemia (high levels of ammonia in the blood). However, the mechanisms involved in both learning and how liver disease leads to learning impairment are unclear.
In a new study led by Vicente Felipo of the Laboratory of Neurobiology at the Fundacion Valenciana de Investigaciones Biomedicas in Valencia, Spain and published in the February 2005 issue of Hepatology, researchers hypothesized that impaired learning was due to a defect in the glutamate-nitric oxide-cGMP pathway in the brain and that administering sildenafil to increase cGMP would restore learning ability. Sildenafil, commonly known as Viagra, is known to prevent the destruction of cGMP and allow it to accumulate in the body. Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD), published by John Wiley & Sons, Inc. is available online via Wiley InterScience at http://www.interscience.wiley.com/journal/hepatology.
Researchers examined four groups of rats in their study: rats in which they constructed portacaval shunts (a treatment used to treat high blood pressure in the liver due to liver disease that is believed to be one of the causes of hepatic encephalopathy, and also a model of chronic liver failure in rats); rats with portacaval shunts that were given sildenafil; rats that were fed an ammonium-containing diet; and rats that were fed the diet and given sildenafil. They also used control groups consisting of rats fed a normal diet both with and without sildenafil. All animals were subjected to a maze learning test four weeks following surgery or from the date when drug treatment began. Levels of both cGMP and ammonia in brain were measured using a microdialysis probe.
Results showed that while rats with the portacaval shunt showed a reduced learning ability, treatment of shunted rats with sildenafil restored their ability to learn. Tests showed that the concentration of cGMP was reduced in the extracellular fluid in brains of shunted rats compared with controls and that treatment with sildenafil restored levels of cGMP in these animals. In addition, further tests showed a reduction of 74 percent in the function of the glutamate-nitric oxide-cGMP pathway in shunted rats, while treatment with sildenafil significantly enhanced the function of this pathway. These evaluations were also performed on rats with hyperammonemia. Results showed that chronic hyperammonemia significantly reduced the rats ability to learn, but that treatment with sildenafil restored their learning ability. While sildenafil treatment restored levels of cGMP and enhanced the function of the glutamate-nitric oxide-cGMP pathway in hyperammonemic rats, it did not affect ammonia levels.
"The fact that rats with portacaval anastomosis [shunts] or with hyperammonemia without liver failure show the same alterations in the function of the [glutamate-nitric oxide-cGMP] pathway, extracellular cGMP and learning ability indicates that hyperammonemia, which is the only common alteration in both models, is responsible for the alteration of the function of the pathway and, subsequently, of the impairment of learning ability," the authors state. They note, however, that an excessive increase in cGMP may impair learning and that it must be kept high but below a certain threshold to reach maximum learning ability.
The authors conclude: "Although caution must be taken considering the possible deleterious increase in the existing vasodilatation in liver disease by sildenafil, pharmacological manipulation of cGMP in brain by safe procedures may be a useful treatment to restore cognitive and intellectual functions in patients with overt or minimal hepatic encephalopathy."
David Greenberg | EurekAlert!
The most recent press releases about innovation >>>
Die letzten 5 Focus-News des innovations-reports im Überblick:
Mapping the interaction of a single atom with a single photon may inform design of quantum devices
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...