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Neurology Today:
doi: 10.1097/01.NT.0000368128.52159.95
Article

Memantine Improves Symptoms and Pathology in Huntington Mice

FRIEDMAN, ROBERTA PHD

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ARTICLE IN BRIEF

Memantine cut losses in motor skills and maintained protective inclusions in mice that model Huntington disease. A small clinical study suggested the drug has promise; a large international trial is being planned for the disorder.

Memantine (Namenda), a drug used to treat Alzheimer disease (AD), is being explored as a possible therapy for Huntington disease (HD), based on new findings in cellular and animal models of HD.

In a cellular model, memantine maintained protective inclusions and, in a transgenic mouse, the therapy cut losses in motor skills, investigators at the Burnham Institute of La Jolla, CA, reported in the Nov. 15, 2009, online edition of Nature Medicine.

The findings in the living animals that make the mutant huntingtin protein that causes the disease support a role for memantine in HD, the study's senior author Stuart Lipton, MD, PhD, director of the Del E. Webb Neuroscience, Aging and Stem Cell Research Center at the Burnham Institute for Medical Research, told Neurology Today.

Dr. Lipton, who holds multiple worldwide patents on use of memantine for HD and other neurodegenerative disorders, said that investigators led by his collaborator, Michael Hayden, MD, PhD, of the University of British Columbia in Vancouver, will meet in Oslo in March with other scientists and clinicians from North America and Europe to explore the feasibility of a larger clinical trial of memantine for HD.

He noted that memantine had been used in movement disorders in Europe two decades before it was approved by the FDA for use in AD. And in a small open label trial of 27 HD patients, reported in a 2004 supplement of the Journal of Neural Transmission, 30 mg daily of memantine was “suggestive” of slowing disease progression.

In tissue studies, the drug acts as a glutamate receptor-agonist and works best when it is countering the effect of excessive glutamate acting on receptors located outside the synapse. These receptors are on the dendrites and cell bodies of neurons. Because memantine relatively spares synaptic N-methyl-d-aspartate-type (NMDA) glutamate receptors, Dr. Lipton said, neurotransmission is preserved.

In the current study, the investigators found that cells from the cerebral cortex and striatum of HD mice were more likely to die if the extrasynaptic NMDA glutamate receptors were activated; but they were protected from cell death if the synaptic NMDA receptors were stimulated. The researchers analyzed the actions at the two locations by recording from the cells and using specific drugs to target each type.

Activity at the NMDA receptors located in the synapse increased the amount of mutant huntingtin sequestered into the larger clumps or inclusions within the cells.

The investigators then sought to replicate the cellular findings in living mice that showed hallmarks of the disease. Mice expressing mutant human huntingtin were given memantine in drinking water from ages two to 12 months. They received either a 1 mg per kg dose to block extrasynaptic activity but leave synaptic activity relatively spared, or high-dose memantine (30 mg per kg body weight) to act at both extrasynaptic and synaptic receptors.

The volume of the striatum, the protective formation of larger inclusions, and the motor ability of mice tested by “rotarod” running improved in the low dose group, but not in the animals given the higher dose.

Part of the attempt to clump disease protein within neurons turns out to be helpful, said Dr. Lipton. “This is probably an effort to wall off the bad protein. It's the smaller, soluble oligomers or microaggregates that escape this process, attaching to other proteins in the cell and impeding cellular functions,” Dr. Lipton said.

“Synaptic activity turns on a series of pathways that try to protect the cell and increase the larger, protective clumps,” Dr. Lipton explained. “Excessive extrasynaptic activity works in the opposite direction, towards the demise of the cell.” The molecular pathways controlled by this electrical activity are unique to the cortical and striatal structures that are destroyed in HD, he noted.

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EXPERTS COMMENT

“This report provides another piece in the puzzle of how mutant huntingtin protein may have adverse consequences on cell function and vitality,” said Ira Shoulson, MD, chair of the Huntington Study Group, and professor of neurology, medicine, pharmacology and physiology at the University of Rochester School of Medicine, NY, in an e-mailed comment. “These findings also add to our therapeutic leads for developing treatments that make a difference for Huntington disease patients and families.”

Jon W. Johnson, PhD, professor of neuroscience at the University of Pittsburgh, who has studied the molecular details of memantine pharmacology in blocking ion channels in the NMDA receptor, noted that memantine is well tolerated and was used in the 1980s in Europe. “At the time they thought it acted mainly at dopamine receptors,” Dr. Johnson said. Memantine was found to inhibit NMDA receptors in 1989, and was approved to treat AD in 2003.

The small study in HD cited by the investigators should be extended, he said. “I think the idea that it would be useful has a good foundation,” Dr. Johnson said. “It's a big advantage that memantine has already gone through clinical trials in AD. We have such poor treatments for HD that even a small improvement, such as we get in AD, would be important.”

Carlos Cepeda, PhD, research professor of physiology at the Semel Institute at the University of California-Los Angeles, noted that cell cultures are an important first step toward sorting out the roles of receptors in HD, but he emphasized that they may not behave exactly the way cells do in living animals.

“Memantine has great potential, it has been tried in Alzheimer disease and in other neurodegenerative disorders, with some outcomes more promising than others,” he said, “So far, it has not been proven in the clinic that it is the best choice in Huntington disease.”

“The AMPA glutamate receptor is kind of forgotten” in this study, and it is also involved in excitotoxicity that is believed to produce the damage in HD, Dr. Cepeda said. He added that the study authors do not seem to make enough of a distinction between cells from the cortex and striatum. “I would like to see what happens in co-cultures of cortical and striatal neurons,” he said.

In an Aug. 19, 2009, study in the Journal of Neuroscience, “we demonstrated that changes in vivo in the mouse model are region specific and time dependent,” Dr. Cepeda said. The connections from cortex to striatum seem to decrease as the disease progresses in the mouse and there is a decrease in spontaneous synaptic activity in the striatum, but just the opposite in the cortex, where the glutamate activity goes up at synapses.

Dr. Cepeda noted that epilepsy occurs in HD, especially in the juvenile form. “If there were a way to stimulate the activity just in the striatum without risking epileptic activity in the cortex,' he said, “that would be a great advance.”

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References

Okamoto SI, Pouladi MA, Lipton SA, et al. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 2009; E-pub 2009 Nov 15.

Kotermanski SE, Wood JT, Johnson JW. Memantine binding to a superficial site on NMDA receptors contributes to partial trapping. J Physiol 2009;587(Pt 19):4589–4604. E-pub 2009 Aug 17.

Cummings DM, André VM, Levine MS, et al. Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease. J Neurosci 2009;29(33):10371–10386.

Beister A, Kraus P, Gerlach M, et al. The N-methyl-D-aspartate antagonist memantine retards progression of Huntington's disease. J Neural Transm Suppl 2004;(68):117–122.

©2010 American Academy of Neurology

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