Drug could improve learning in Down's syndrome

By Mike Nagle

- Last updated on GMT

Related tags: Action potential, Neuron

A chemical that has historically been used to study epilepsy could
also improve the learning ability of people with Down's syndrome,
according to US scientists.

Scientists at Stanford University School of Medicine and Lucile Packard Children's Hospital found that a chemical called pentylenetetrazole (PTZ) substantially improved learning and memory in mice with Down's syndrome symptoms. The effects also lasted for months after the treatment was discontinued and the researchers are now considering a human clinical trial. In the US and the UK, more than 400,000 people have Down's syndrome and it is estimated that around one in every 750 to 1000 babies are born with the genetic condition, according to the US National Down Syndrome Society and the UK Down's Syndrome Association. It is caused by the presence of all or part of an extra 21st chromosome and people with the syndrome will have a degree of learning difficulty, among other health problems. "This treatment has remarkable potential," said Craig Garner, PhD, professor of psychiatry and behavioural sciences and co-director of Stanford's Down Syndrome Research Centre. "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's syndrome might be treated." The research team fed Ts65Dn mice, a well-established model for Down's syndrome, 17 daily doses of milk containing PTZ. They found that the mice were significantly better at identifying objects. For example, when shown two similarly sized objects, the Ts65Dn mice treated with PTZ behaved like wild-type mice and spent longer investigating an object if they had previously seen it. A second test in a T-shaped maze showed that mice treated with PTZ were also more methodical, exploring one arm then the other, in a similar fashion to the normal mice. "Somehow the drug treatment creates a new capacity for learning," said Garner, although he warned 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 PTZ blocks the action of an inhibitory neurotransmitter called gamma-aminobutyric acid (GABA). By binding to receptors in neurons, GABA helps the flow of charged particles in or out of the cell, resulting in the action potentials that are used to transmit information between tissues. Normally, the brain maintains a precise balance between neuronal excitation and inhibition that allows efficient learning. However, it is thought that people with Down's syndrome have too much GABA-related inhibition, and this makes it more 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." However, too much PTZ can cause seizures, leading the chemical to be used to study epilepsy in animals. Although briefly tested as a cognitive enhancement therapy in the 1950s, the US Food and Drug Administration (FDA) withdrew approval for the use of PTZ in humans in 1982. "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, a graduate student in Garner's laboratory, who conducted the research. The team found that an effect was only seen after several days of dosing and the effects continued after treatment stopped. In this way, PTZ behaved like some well-known psychiatric medications, according to the scientists. "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. Although PTZ has been used in humans previously, which may help when planning a clinical trial, the team stressed that appropriate dosing levels and schedules had not been established and the drug did not improve the learning ability of wild-type 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." Treatments for Down's are few and far between, and are generally developed for other disorders. Both Aricept (donepezil), from Eisai and Pfizer, and Novartis Pharmaceuticals' Exelon (rivastigmine) were developed for Alzheimer's sufferers but could be used to treat Down's syndrome by slowing the progression of the genetic condition.

Related topics: Preclinical Research

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