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Drug Removed by FDA in 1982 Improves Learning in Down Syndrome Mice

Samson, Kurt

doi: 10.1097/01.NT.0000269122.67974.02
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ARTICLE IN BRIEF

  • ✓ Down syndrome mice treated for two weeks with low-dose pentylenetetrazol performed as well as their normal counterparts in two basic learning and memory tests, and the improvements lasted for at least two months after treatment ended.

Low doses of a drug that was taken off the market 25 years ago significantly improves learning and memory in a mouse model of Down syndrome, according to a new study published online Feb. 25 in advance of the print edition of Nature Neuroscience.

Figure. D

Figure. D

Down syndrome mice treated for two weeks with low-dose pentylenetetrazol (PTZ) performed as well as their normal counterparts in two basic learning and memory tests, and the improvements lasted for at least two months after treatment ended.

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HOW PTZ WORKS

PTZ blocks the activity of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter that plays a pivotal role in learning by maintaining the precise balance between neuronal excitation and inhibition in mice and humans. Down syndrome patients have too much GABA-related inhibition, making it difficult for them to process information.

Postmortem brain samples have revealed structural changes associated with GABA inhibition in older Down syndrome patients — and the activity of GABA in cognitive decline in both Down syndrome and Alzheimer disease has been documented in an experimental mouse model that mimics the disorders.

PTZ was used to treat confusion and functional memory disorders in elderly patients, and to induce seizures in epileptic patients for electroencephalographic evaluation. The FDA determined that its efficacy was questionable in light of possible seizure risks, and ordered it removed from the market in 1982.

“In general, learning involves neuronal excitation in certain parts of the brain,” explained Craig C. Garner, PhD, a professor of psychiatry and co-director of the Down Syndrome Research Center at Stanford's Lucile Packard Children's Hospital, who led the research with Fabian Fernandez, a graduate student in his laboratory.

“Research on Down syndrome has been stagnant until the past decade,” but has now illuminated the role and action of GABA, Fernandez told Neurology Today in a telephone interview.

“A lot of research seems to have converged,” he said. “Over-inhibition of neuronal excitation contributes to intellectual disability in Down syndrome. I thought it might be possible to harness this excitation effect, which at higher doses can be pathological, to benefit people with Down syndrome.”

The researchers hypothesized that a GABA inhibitor might also promote neuronal balance in mental retardation, and became intrigued by PTZ as they reviewed earlier studies of the drug.

The experimental mice — a TS65Dn strain with excessive inhibition of the dentate gyrus, an area important for learning and memory — were significantly better able to identify new objects and navigate a maze — tasks that simulate difficulties faced by children and adults with Down syndrome — after 17 daily doses of milk containing PTZ.

The Ts65Dn mouse exhibits brain function abnormalities very similar to those in human Down syndrome and Alzheimer disease. It was bred with an extra copy of the mouse chromosome that corresponds to human chromosome 21. People with Down syndrome are trisomic for chromosome 21 — the mouse has trisomy of chromosome 16 (J Neurosci 2004;24:8153–8160).

“The tricky part is that these mice tend to have a propensity for stress, so we had to use experiments that wouldn't stress them out and confound the results,” he told Neurology Today.

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STUDY PROTOCOLS

Fernandez gave low daily doses of PTZ and investigated the animals' responses to unfamiliar objects and a T-shaped maze. In the first test, he allowed the animals to explore two similar but different objects for 15 minutes, then exposed them again a day later to one of the objects they had already seen and a new one. Although normal mice spent more time investigating the new object, untreated Down syndrome mice showed no preference for either object.

In the maze test, the animals were habituated to the long arm of a T-shaped maze and then allowed to explore it. The normal mice tended to investigate first one, then the other arm of the maze, while untreated Down syndrome mice were less methodical.

After 17 days of treatment, however, the Down syndrome mice performed more like the others on both tests. That this improvement lasted for two months after treatment stopped is important, Dr. Garner told Neurology Today in a telephone interview. “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.”

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PLANS FOR A CLINICAL TRIAL

Although studies of promising drug treatments in Down syndrome mice have a poor track record in human subjects, Dr. Garner is planning a clinical trial.

“The idea is test the idea,” he said. “But it will be a long process. Even though PTZ was approved before, we have to start all over again.”

And even if PTZ does not work out, it has “opened a window” showing that treatment can improve learning in Down syndrome, he noted.

GABA antagonists with similar action could also be developed to treat similar disorders, like Fragile X syndrome and neurofibromatosis, according to Fernandez.

However, he cautioned that these improvements could diminish with time as older and more drug-experienced neurons are replaced by younger cells. The researchers strongly cautioned individuals against experimenting with PTZ and similar compounds on their own because appropriate doses and schedules have not yet been determined.

Nonetheless, PTZ was used for years before its withdrawal and its safety profile is bolstered by “at least 30” studies in the medical literature, Fernandez noted. There are safety data showing oral doses up to 10 mg/kg are safe. Patients have taken the drug at lower doses for 10 years without serious side effects, he said.

“There's a lot of anecdotal evidence that this should be feasible, although any treatment for human patients is years away,” said Fernandez.

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CAUTIOUS OPTIMISM

David Patterson, PhD, a professor of biological sciences at the University of Denver and senior scientist at the Eleanor Roosevelt Institute, studies the genetics of cognitive and behavioral disabilities in people with Down syndrome. He told Neurology Today in a telephone interview that he is optimistic about the findings.

“There's a long way to go, but this is the first study to show such a big change in these mice with a drug,” he said. “We don't know if it will work in humans yet, but there are a lot of similarities in the biochemistry of Down syndrome in humans and mice.”

Dr. Patterson was a member of the research team that did the initial mapping and characterization of chromosome 21, the smallest human chromosome and the one associated with Down syndrome, epilepsy, amyotrophic lateral sclerosis, and Alzheimer disease (Nature 2000;405:311–321).

Although PTZ was removed from the market for lack of efficacy in treating seniors with cognitive dysfunction and other disorders, neither he nor Fernandez were aware of any studies in Down syndrome patients.

“That's one of the issues that needs to be addressed,” said Dr. Patterson. “It might be possible to use it, but it would be premature and unwise, not to mention dangerous, for people to start taking it on their own until clinical trials have been performed.”

That improvement in the mice lasted for several months after treatment was halted could also pose problems, he added. “If someone were to have a bad reaction, it's not like we would be able to simply stop treatment. That's another reason for caution.”

Although the effect was “remarkable” in the mice, Dr. Patterson said he would be “surprised if it proves to be the entire solution. There are many aspects to this syndrome and a lot more altered genes on chromosome 21 that this drug would not affect.”

If the findings are replicated, additional testing in other cognitive domains might one day answer additional questions about the syndrome, he noted. “This study is an important contribution that needs to be followed up vigorously.”

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THE MOUSE MODEL OF DOWN SYNDROME

Ts65Dn mice exhibit cognitive dysfunction that implicate the hippocampus, as well as marked deficits in hippocampal long-term potentiation and widespread abnormalities of synaptic structure, all of which are important features in Down syndrome. The mouse is also used to study functional links of the amyloid precursor protein, which is involved in neurodegeneration in Alzheimer disease and neuroinflammatory responses.

Research suggests both presynaptic elements and postsynaptic elements are enlarged in many brain regions in the mice, with involvement of the motor cortex, sensory cortex, and hippocampus and, in many cases, enlarged axonal terminals are in contact with enlarged dendritic spines. The changes are present early in development and persist throughout the life of the mouse.

The brain of virtually every person with Down syndrome older than 40 years shows neurodegeneration identical to Alzheimer disease, and evidence suggesting a reduction of cerebral gamma-aminobutyric acid (GABA) neurons in Alzheimer disease has been reported. GABA antagonists are currently in clinical trials for Alzheimer disease.

Unfortunately, the Ts65Dn mouse is difficult and expensive to breed. Congress and the NIH have been asked to increase the supply by raising federal funding. Recently NIH approved more funding for production of the Ts65Dn mouse over a two-year period.

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REFERENCES

• Fernandez F, Morishita W, Garner C, et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nature Neuroscience 2007; E-pub 2007 Feb. 25.
    • Kleschevnikov A, Belichenko V, Mobley W, et al. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J Neurosci 2004;24:8153–8160.
    • Hattori M, Fujiyama A, Yada T, et al. The DNA sequence of human chromosome 21. Nature 2000;405 (6784):311–319.
    • Reynolds G, Warner C, Mercer K. Alzheimer-like cortical amino-acid changes in elderly Down's syndrome patients. J Neural Transmission 1989;1:1435–1463.
      • Wisniewski, KE, Dalton, AJ, and Wisniewski HM, et al. Alzheimer's disease in Down's syndrome: clinicopathologic studies. Neurology 1985; 35:957–961.
        ©2007 American Academy of Neurology