HD Lighthouse Contributing Editor's Comment: The excitotoxicity theory of Huntington's Disease has been popular among researchers but has yet to yield treatments. The idea is that the overstimulation of N-methyl-d-aspartate (NMDA)-type glutamate receptors causes a variety of problems including excessive calcium in the associated ion channels and eventually leads to cell death. Researchers know that this is a problem in stroke and brain injury, and have reason to believe that it also occurs in chronic neurological diseases albeit in a slower manner.

Treating excitotoxicity is tricky business though. Glutamate is an extremely important neurotransmitter which rapidly conveys information from our senses as well as motor commands from neuron to neuron. Blocking the receptors altogether is likely to cause serious side effects and that may be why the glutamate blockers lamotrigine and remacemide did not slow progression of HD in clinical trials. Riluzole doesn't look very promising either and requires monitoring for liver toxicity. It seems likely that these drugs' interference with the normal activity of glutamate and the NMDA receptors accounts for the disappointing results in clinical trials.

Dr. Lipton, however, has shown that memantine blocks excessive but not normal activity -- hence the drug's promise in treating neurodegenerative disorders. Memantine has been approved for Alzheimer's patients in the U.S. and a number of neurologists are now prescribing it for Huntington's patient based on its success with AD as well as the positive report from an open label study that we reported here. My husband started taking it in November. The Lighthouse will continue to follow news about this drug closely.

Read the whole article here: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15717010
--Marsha L, Miller, Ph.D.
Posted to the HDL: 14 Mar 2005

Failures and Successes of NMDA Receptor Antagonists: Molecular Basis for the Use of Open-Channel Blockers like Memantine in the Treatment of Acute and Chronic Neurologic Insults.

Excitotoxicity, defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, has been implicated as one of the key factors contributing to neuronal injury and death in a wide range of both acute and chronic neurologic disorders. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors and hence excessive Ca(2+) influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function; potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of diseases including stroke and neurodegenerative disorders such as Huntington's disease. In contrast, studies in my laboratory were the first to show that memantine, an adamantane derivative, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Past clinical use for other indications has demonstrated that memantine is well tolerated, and it has recently been approved in both Europe and the USA for the treatment of dementia of the Alzheimer's type. Clinical studies of the safety and efficacy of memantine for other neurological disorders, including glaucoma and other forms of dementia, are currently underway. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than does memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, in addition to its ion channel, that could potentially be used for safe but effective clinical intervention.

Tracked on the Lighthouse:
memantine
glutamate
excitotoxicity
NMDA receptor antagonists

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Source: Neurorx. 2004 Jan;1(1):101-110.

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