Memantine tackles premature brain aging

Memantine regulates glutamate, a chemical involved in information processing, storage and retrieval

It is thought that glutamate – the brain’s primary excitatory neurotransmitter – plays a significant role in the neuronal cell death that is common to all neurodegenerative diseases. As neurons are damaged – in Alzheimer’s, for example, by the deposition of amyloid – that damage leads to an excess release of glutamate, which neuroscientists refer to as ‘overexcitation’. By blocking the action of glutamate at NMDA receptors, Memantine directly short-circuits the overexcitation.

Memantine’s unique way of working

The majority of current drugs that treat Alzheimer's disease, such as Galantamine, do so by inhibiting an enzyme called acetylcholinesterase. This enzyme breaks down the brain neurotransmitter- acetylcholine. It is acetylcholine that is badly affected in Alzheimer's patients.

But Memantine works very differently. It appears to protect the brain’s nerve cells against glutamate, a messenger chemical released in excess amounts by cells damaged by Alzheimer’s disease or certain other neurological disorders. When glutamate binds to N-methyl-D-aspartate (NMDA) receptors, this attachment permits calcium to flow freely into the cell. Sustained elevation of glutamate leads to chronic overexposure to calcium, which in turn leads to cell degeneration. Memantine may prevent this destructive sequence by filling the NMDA receptor sites.

Memantine and the premature aging of the brain

Although Memantine has been in use in Germany for nearly 10-years, it is only recent clinical trials that have highlighted many of its unique properties, particularly for its use in age-related dementia.

As Memantine offers Alzheimer’s sufferers improvements in memory, attention, reason, language and the ability to perform simple tasks, there are potential benefits for non-Alzheimer’s sufferers too.

Over stimulation of NMDA receptors is referred to as excitotoxicity. Biochemist James South, stated in his article, that there are daily factors in everyday lives, many of them present in certain diets, that cause over excitation of NMDA receptors. Most notably these are some artificial sweeteners, flavor enhancers, (especially MSG) and even hydrolyzed vegetable proteins.

As Alzheimer's disease, vascular and mixed dementia are the commonest forms of dementia in older people, the question is being asked in some circles - Are they nothing more than the result of a long term exposure to a bad diet? A diet, that leads to over stimulation of NMDA receptors? We don't know the answer yet, but we do know enough to take some simple steps to try and avoid some of the potential problem areas.

By understanding, and doing what is necessary to cope with, the brain's tendency to excitotoxically ‘melt down’ – including use of Menantine if necessary - we can avoid the aging effects of excitotoxicity.

Memantine and Alzheimer’s disease

As already mentioned, Memantine appears to work by regulating the activity of glutamate, one of the brain’s specialized messenger chemicals involved in information processing, storage, and retrieval. Glutamate plays an essential role in learning and memory by triggering NMDA receptors to allow a controlled amount of calcium to flow into a nerve cell, creating the chemical environment required for information storage.

Excess glutamate, on the other hand, overstimulates NMDA receptors to allow too much calcium into nerve cells, leading to disruption and death of cells. Memantine may protect cells against excess glutamate by partially blocking NMDA receptors.

Memantine’s action differs from the mechanism of the cholinesterase inhibitors that were previously approved in the United States for treatment of Alzheimer symptoms. Cholinesterase inhibitors temporarily boost levels of acetylcholine, another messenger chemical that becomes deficient in the Alzheimer brain.

Clinical Studies

There have been numerous clinical studies involving Memantine and Alzheimer's disease. One clinical study, conducted under the double-blind placebo-controlled method, concluded that Memantine is a safe drug and may be useful for treating Alzheimer's disease, vascular and mixed dementia of all severities.

Even in elderly patients with general cognitive disturbances, (but not yet diagnosed as a specific senile dementia), Memantine has been shown to enhance vigilance and improve short-term memory and concentration. Furthermore, the tolerance of the drug was good in virtually all cases.

After 28-weeks of treatment, a French study with 321 Geriatric patients in 2002 concluded that; "Patients with mild to moderate dementia had improved cognition consistently at 20mg/day Memantine, with no deterioration in functioning and behavior." Furthermore, the study stated that; "Memantine was devoid of concerning side effects."

The beneficial effects of Memantine can be seen quickly. For example, a study with 66 patients aged 65 to 80 and all suffering from mild to moderate dementia, indicated that after just 14 days there was significant improvement when compared to placebo. At 42-days the effects were even more pronounced and the study announced that, "It was particularly striking in the daily-living tests, of the patients considerable improvement achieved in the quality of performing tasks under Memantine treatment."

Perhaps most interesting of all has been the reports of Memantine's efficacy in late-stage Alzheimer's disease. This distressing phase of the disease is one where other treatments are not currently available. For example, a Swedish study in 1999 confirmed that, "The results of the trial support that Memantine treatment leads to functional improvement and reduces care dependence in severely demented patients."

A more recent study with 252 patients studied over a period of 28 weeks, receiving either placebo or 20mg/day of Memantine. It was clearly noted that Memantine reduced the clinical deterioration in moderate to severe Alzheimer's disease. Dr. Hans Joerg Moebius stated that, "These promising results represent a breakthrough in terms of significant patient and caregiver benefit by Memantine, in the untapped therapeutic area of advanced dementia. In addition, compared to other anti-dementia drugs, Memantine showed an excellent safety and tolerability profile."

Other beneficial effects of Memantine

Studies indicate that Memantine could have beneficial effects for sufferers of Parkinson's disease. One such clinical study, concluded with the statement, “The results suggest that Memantine may improve Parkinsonian symptoms independently of dopaminergic drugs.”

Further studies suggest that Memantime could be used to treat alcoholism. It is though that NMDA receptors could have a role in alcoholism and that Memantine be used as an anti-craving drug.

There are also reports that Memantine could be efficacious in the alleviation of some intense pain conditions, particularly for painful neuropathy, with one trial at 40mg/day Memantine, statistically and significantly alleviating night time pain for patients.

There are even on-going trials utilizing Memantine for glaucoma and ocular hypertension, as well as AIDS related dementia.

Whilst further research is needed in these areas, it is becoming apparent that NMDA receptors have a number of negative effects when they are over-stimulated, and that antagonists such as Memantine, are set to become important factors in the management and control of numerous debilitating conditions.

Dosage:
Take 20mg per day. To lower the risk of side effects the daily dosage should gradually be increased from 5mg to 20mg over four weeks. Memantine can be taken with other Alzheimer’s drugs such as Aricept, Exelon, and Reminyl (galantamine), as it works in a different manner.

Caution:
Memantine use should be carefully monitored by your doctor if you have a history of seizures or have recently had a heart attack, kidney disease or untreated hypertension. Memantine may interact with some other drugs such as Dextromethorphane, Cimetidine, procainamide, hydrochlorothiazide, anticholinergics, anticonvulsives, barbituates or dopaminergic antagonists like L-dopa or bromocriptine. Make sure the doctor knows what else the person with dementia is taking

Memantine has been available for over 10 years in Germany and is the most frequently prescribed treatment for dementia.

Research suggests that memantine is clinically safer than many other NMDA antagonists in treating neurodegenerative diseases.  It's believed that memantine's neuroprotective effects are due to blocking the NMDA receptor against excitotoxicity (overstimulation of glutamate) without upsetting the neurotransmitter's normal functioning as some other drugs do.
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Clinical data, demonstrating the ability of memantine to preserve cognition and daily functioning and delay the rate of decline in patients with advanced Alzheimer disease, was presented at a major neuropsychopharmacology conference held in Hawaii in December 2001. 

A second study presented at this meeting shows memantine's potential neuroprotective and cognition-enhancing role in beta-amyloid-induced neurotoxicity in the brain.  Plaques containing beta-amyloid are believed to be a key contributing factor in the development of Alzheimer disease. 

Memantine is currently under Phase III development in the United States by Forest Laboratories.  Researchers believe that Memantine's mechanism of action is distinctly different from agents currently available to treat Alzheimer disease.  All of these agents increase the availability of the neurotransmitter acetylcholine for viable neurons, whereas memantine is thought to prolong or preserve neuronal viability. 

Research suggests memantine may exert a neuroprotective effect and improve cognition when beta-amyloid toxicity is present. Previous research suggests that formation of beta-amyloid containing plaques in the brain, and progressive nerve-cell death, are primary causes of the cognitive and functional deteriorations of Alzheimer disease. 
In the study researchers observed the degeneration of neurons in rat brains following injections with beta-amyloid. Animals treated with memantine, however, had significant reductions in the amount of neuronal degeneration and performed better on other key measures of behavioral and functional changes. The researchers concluded that memantine has the potential to protect against neuronal degradation in rats and may slow the learning impairment caused by beta-amyloid. 

The investigational agent memantine is thought to provide a neuroprotective effect in both the central and peripheral nervous systems by blocking the NMDA receptor against the effects of chronic excess amounts of glutamate, but without interfering with the role of glutamate in normal neuronal functioning. The mechanism of action of memantine differs from earlier investigational NMDA antagonists that interfered with normal glutamate functioning due to their high affinity to the receptor. 

Glutamate plays an integral role in neural pathways associated with learning and memory, including the movement of electrical signals across up to 70% of the central nervous system's excitatory synapses. Excessive amounts of glutamate can, however, damage cells by causing overstimulation. The excitotoxicity produced by glutamate is hypothesized to be responsible for the neuronal cell death observed in Alzheimer, and possibly in other diseases that involve neurodegeneration. 

The recommended dose of memantine for adults and elderly patients is 20mg (2x 1 tablet). In order to reduce the risk of side effects this dose is achieved gradually by the following daily treatment program.

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