Will a combination drug cure Alzheimer's disease?
New drug restores nerve synapses in Alzheimer's disease
LifeSciencesToday based on Sanford-Burnham: Reversing the loss of brain connections in Alzheimer's diseaseScientists of the Sanford-Burnham Medical Research Institute (Sanford-Burnham Medical Research Institute) have developed the first experimental drug that restores nerve synapses lost due to Alzheimer's disease.
The drug, called NitroMemantine, combines two FDA–approved drugs to stop a destructive cascade of changes in the brain that destroys connections between neurons - the causes of memory loss and cognitive disorders.
The results of a ten-year study conducted by Stuart Lipton, MD, PhD, professor and director of the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research (Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research) and a practicing neurologist-clinician, suggest that NitroMemantine can restore synapses – connections between nerve cells, – progressively lost during the development of Alzheimer's disease. The study is published in the Proceedings of the National Academy of Sciences (Talantova et al., Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss).
The impact not on beta-amyloid plaques and neurofibrillary tangles – approaches that have not been crowned with any significant clinical success - but on a lower target "is very interesting, because everyone is now looking for methods of treating this disease at its earlier stage," says Professor Lipton. "Our results actually mean that it is possible to intervene in the disease not only at its early, but also at a slightly later stage." This means that it is possible to restore synaptic connections in a patient with Alzheimer's disease even when plaques and tangles have already formed in his brain.
In their study conducted on animal models, as well as brain cells derived from human stem cells, Professor Lipton and his group identified and described the pathway leading to synaptic damage in Alzheimer's disease. The researchers found that beta-amyloid peptides, considered to be the direct culprits of synapse damage, actually induce the release of an excessive amount of the neurotransmitter glutamate from astrocyte brain cells located next to neurons.
Normal levels of glutamate activate cognitive processes – memory and learning ability – but excessive levels of it are harmful. In patients suffering from Alzheimer's disease, excess glutamate activates extrasynaptic glutamate receptors, known as ENMDA receptors (eNMDARs), (NMDA - N–methyl-D-aspartate), hyperactivation of which, in turn, leads to the loss of synapses.
Earlier, Professor Lipton's laboratory discovered how to target eNMDA receptors with a drug called memantine in order to lower the hyperactivity observed in Alzheimer's disease. This patented work contributed to the approval in 2003 of memantine as a drug for the treatment of Alzheimer's disease with moderate to severe dementia. However, the effectiveness of memantine is limited. As the researchers found, the reason for the insufficient effectiveness of the drug was that a positively charged memantine molecule is repelled by a similar charge inside a diseased neuron. Accordingly, memantine is also repelled by its target, the eNMDA receptor, on the surface of neurons.
The researchers found that a fragment of a molecule of nitroglycerin – the second FDA–approved drug commonly used to relieve angina in patients with coronary heart disease - can interact with another site on NMDA receptors discovered by Professor Lipton's group. The new drug is a synthesis of this fragment of nitroglycerin with memantine. Since memantine binds selectively enough to eNMDA receptors, it simultaneously makes this receptor a target of nitroglycerin.
Thus, by combining two approved drugs, Lipton's laboratory has created a new multifunctional drug. By suppressing the function of hyperactive eNMDA receptors on affected neurons, NitroMemantine restores interneuronal synapses.
Before a working variant of the combined compound was found, researchers developed 37 of its derivatives.
"In our article, we show that memantine's ability to protect synapses is limited," Professor Lipton comments on his work, "but NitroMemantine returns the number of synapses to normal after several months of treatment of mice with Alzheimer's disease models. In fact, the effect of this new tool begins within a few hours."
Today, scientists are forced to admit that clinical trials of drugs targeted at beta-amyloid plaques and neurofibrillary tangles have not been successful. "It's disappointing because I see real patients suffering from dementia. However, I hope that NitroMemantine will prove its effectiveness in clinical trials and give new hope to patients with both early and late–stage Alzheimer's disease," concludes Professor Lipton.
Portal "Eternal youth" http://vechnayamolodost.ru21.06.2013