Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Drug treatment improves learning in mice with Down syndrome symptoms

27.02.2007
A once-a-day, short-term treatment with a drug compound substantially improved learning and memory in mice with Down syndrome symptoms, say researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital.

What’s more, the gains lasted for months after the treatment was discontinued. The researchers are now considering a clinical trial to test whether the compound has a similar effect in humans with Down syndrome.

"This treatment has remarkable potential," said Craig Garner, PhD, professor of psychiatry and behavioral sciences and co-director of Stanford’s Down Syndrome Research Center. "So many other drugs have been tried that had no effect all. Our findings clearly open a new avenue for considering how cognitive dysfunction in individuals with Down syndrome might be treated." The center was created by researchers at Stanford and Packard Children’s in 2003 to rapidly translate research discoveries into useful treatments for people with Down syndrome.

The research, which will be published Feb. 25 in the advance online edition of Nature Neuroscience, was conducted by Fabian Fernandez, a graduate student in Garner’s laboratory. Fernandez found that affected mice were significantly better able to identify novel objects and navigate a maze ­ tasks that simulate difficulties faced by children and adults with Down syndrome ­ after being fed 17 daily doses of milk containing a compound called pentylenetetrazole, or PTZ. Treated mice performed as well as their wild-type counterparts for up to two months after drug treatment was discontinued.

... more about:
»Fernandez »PTZ »compound »doses »excitation »wild-type

"Somehow the drug treatment creates a new capacity for learning," said Garner, who cautions that this new ability may decay over longer periods of time as older, drug-experienced neurons are replaced by younger cells.

The researchers believe that the key to the improvement lies in the fact that PTZ blocks the action of an inhibitory neurotransmitter called GABA. Normal brains maintain a precise ratio between neuronal excitation and inhibition that allows efficient learning. In contrast, it’s thought that Down syndrome patients have too much GABA-related inhibition, making it difficult to process information.

"In general, learning involves neuronal excitation in certain parts of the brain," said Garner. "For example, caffeine, which is a stimulant, can make us more attentive and aware, and enhance learning. Conversely, alcohol or sedatives impair our ability to learn."

But as any overenthusiastic college student can attest, too much caffeine can backfire. The same is true with high doses of PTZ, which can cause seizures. In fact, after some brief, inconclusive studies on cognition enhancement in elderly or mentally impaired people in the 1950s, PTZ has been primarily used for the study of epilepsy in animals. In 1982 the FDA withdrew approval for the use of PTZ in humans because no clear clinical benefit had been established. That is, until now.

"My idea was that it might be possible to harness this excitation effect, which at higher doses can be pathological, to benefit people with Down syndrome," said Fernandez.

More than 300,000 people nationwide have Down syndrome, which is caused by an extra copy of chromosome 21. It is the leading cause of mental retardation in the country, and it is also associated with childhood heart disease, leukemia and early onset Alzheimer’s disease. The researchers used a mouse model of Down syndrome for their study in which about 150 genes are triplicated. The mice exhibit many of the cognitive problems that afflict human Down syndrome patients.

Fernandez gave low daily doses of PTZ and investigated the animals’ responses to unfamiliar objects and a T-shaped maze. In the first example, he allowed the animals to explore two similarly sized, yet obviously different, objects for 15 minutes. Twenty-four hours later he exposed the same animals to one of the previously seen objects and a third, never-before-seen object. Although wild-type mice spent more time investigating the new object, untreated Down syndrome mice showed no preference for either object.

In the maze test, mice were habituated to the long arm of a T-shaped maze and then allowed to explore. Wild-type mice tended to investigate first one, then the other arm of the maze, while untreated Down syndrome mice were less methodical. However, the Down syndrome mice performed more like their wild-type counterparts on both tests after 17 days of PTZ treatment.

The researchers discovered two interesting things when testing the mice: daily doses were required for several days before any effect was detected, and, once established, the effect lasted for up to two months after the drug was withdrawn. In fact, the drug’s activity profile mirrored that of some well-known psychiatric medications.

"This suggests that it’s not just the removal of the excess inhibition that allows learning to occur, but that we’re instead strengthening synapses through some type of long-lasting neuronal adaptation," said Garner.

A key component of enduring neural change associated with memory is known as long-term potentiation. In general terms, once a threshold of activating signals has been achieved, a neuron becomes permanently more sensitive to excitation. Although long-term potentiation has been shown to be impaired or absent in the brains of Down syndrome mice, postdoctoral scholar Wade Morishita, PhD, who works in the Stanford laboratory of professor Rob Malenka, PhD, found that it approached normal levels after chronic PTZ treatment and remained comparable to that in wild-type mice for up to three months after PTZ was discontinued.

PTZ’s history of use in humans is an advantage when planning a clinical trial. However, the compound is not currently approved by the Food and Drug Administration for use in humans. Garner and Fernandez both strongly cautioned individuals against experimenting with the compound or others like it on their own. Appropriate doses and schedules have not yet been determined for humans, and the purity and safety of similar over-the-counter concoctions are questionable. Finally, they emphasized that PTZ treatment did not improve the learning capabilities of normal mice.

"We’re not in the business of cognitive enhancement," said Fernandez. "Basically, we have something that could be one part of the many different medical and environmental interventions that may allow kids with Down syndrome to live more normally."

Louis Bergeron | EurekAlert!
Further information:
http://www.lpch.org
http://www.stanford.edu

Further reports about: Fernandez PTZ compound doses excitation wild-type

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

Im Focus: Newly proposed reference datasets improve weather satellite data quality

UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration

"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Water - as the underlying driver of the Earth’s carbon cycle

17.01.2017 | Earth Sciences

Satellite-based Laser Measurement Technology against Climate Change

17.01.2017 | Machine Engineering

Studying fundamental particles in materials

17.01.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>