Compound Alzheimer’s Drug Could Regenerate Lost Brain Connections

Written by Rachel Barclay on June 18, 2013

A new drug, called NitroMemantine, combines two medicines that are already FDA-approved to create an anti-Alzheimer's super-drug. Unlike most existing Alzheimer’s treatments, NitroMemantine appears to directly target the cellular pathway that causes patients with Alzheimer’s disease to lose important brain connections.

Alzheimer’s disease is one of the leading causes of dementia, affecting approximately five million Americans today. With the ever-growing cost of providing care for ailing seniors, drugs that can offset dementia and keep people healthy into old age are a researcher's dream.

Scientists at Sanford-Burnham Medical Research Institute, led by Dr. Stuart A. Lipton, have devoted a decade of study to understanding just how Alzheimer’s causes the brain to deteriorate. 

Out With the Old, in With the New

Most of what doctors currently know about Alzheimer’s disease comes from observation. Scientists can autopsy the brain of a patient who has passed away from Alzheimer’s and examine tissue samples under a microscope. On that level, the disease is very apparent: clusters of proteins called amyloid beta plaques and neurofibrillary tangles clog the brain, interfering with its ability to send information from one area to another through structures called synapses.

The cause seems obvious—these protein clumps poison or otherwise damage the brain cells that transmit information, called neurons. Drug after drug has been developed to break apart these clumps or prevent them from forming in the first place, but they've met with little success.

"We took a different tack. We said, let's protect the synapses," said Lipton, Scientific Director of Sanford-Burnham and a clinical neurologist at the University of California, San Diego.

Lipton noticed that the damaged cells had high levels of a neurotransmitter chemical called glutamate, a molecule that neurons use to talk to one another. Researchers in the past had assumed this was a result of damage caused by the plaques and tangles, but Lipton thought glutamate might play an active role in neural deterioration.

"The only pathological correlate with how demented one becomes in Alzheimer's is the number of synapses," Lipton explained. "You can have a lot of amyloid protein and not a lot of cognitive deficit."

Through a robust series of experiments in living rats and human brain cells grown in the lab, Lipton’s team seems to have found the answer.

Lipton discovered that the compound drug NitroMemantine not only completely eliminated the loss of synapses caused by the amyloid proteins, but even reversed it. Within six hours, cells were regrowing synapses that had already been lost to Alzheimer's, and the effect was apparent only ten minutes after administering the drug.

The Brain’s Worst Enemy: Itself

Less than one brain cell in ten is a neuron. The rest are cells called glia, which help neurons transmit information faster, protect them from toxins and infections, and perform other vital functions. One type of glial cell is called an astrocyte.

Astrocytes wrap around neurons to protect them. Unlike most of the body’s cells, which can grow back if they die, most of the brain can't grow new cells in adulthood, making protecting existing cells high a priority. By standing between the bloodstream and the neuron they are protecting, astrocytes can filter out any toxins a person might consume in his or her diet and also act as a first line of defense against invading viruses and bacteria.

For more than a century, scientists thought the role of astrocytes was solely protective. New research, including Lipton’s, has shown that astrocytes play a much greater part than previously thought.

Even small amounts of amyloid protein were enough to activate an astrocyte, the researchers found. The astrocytes began releasing glutamate and activating a specific receptor on the neuron they were protecting. Although the exact mechanism is unknown, in each of their trials, Lipton’s team observed the same results: when these glutamate receptors were activated on a neuron, the neuron began to lose its connections and ability to communicate.

An average neuron in the brain has 10,000 connections to other neurons. If a neuron is starved for communication, as is the case in Alzheimer's patients, the neuron will eventually wither and die.

So why do astrocytes cause the brain to lose these key connections? Besides protecting neurons, one of their purposes is to keep the growth of the brain in check. Having too many neural connections has been tied to, among other things, depression, schizophrenia, and bipolar disorder. By preventing overgrowth, astrocytes help keep the brain healthy. In the case of Alzheimer’s, however, it appears this regulation system is overactive and prunes away too many connections.

This is where NitroMemantine comes into play.

Memantine, a drug that is already FDA-approved to treat Alzheimer’s disease, can block glutamate receptors without activating them, so that the glutamate released by the astrocyte has nowhere to go. However, memantine has a strong positive charge, making it slide away from the receptor as if you were trying to force together the south ends of two magnets. This is why drug trials of memantine alone have not proven particularly effective.

Lipton’s team added on a nitro group, taken from another drug called nitroglycerin, which is widely used to treat heart conditions. The nitro group has a strong attraction to the glutamate receptor, allowing memantine to reach the right location and protect the neuron.

Even better, NitroMemantine targets just the glutamate receptors that astrocytes use, and leaves alone the receptors that neurons need to continue communicating with each other.

"The FDA-approved drug memantine, which we previously developed, targets sick nerve cells," Lipton said. "The more disease there is, the better the drug works. These drugs are only there when you need them and when they're done, they leave."

If NitroMemantine proves as effective in living humans as it has in the lab, it could be the first drug to prevent and reverse Alzheimer’s-related brain damage. If Alzheimer’s is caught early enough, with this drug, the patient might never experience dementia at all.

"Now, rather than just barely protecting synapses, at least in the animal models, the new improved drug, NitroMemantine, gets the number of synapses all the way back to normal," Lipton said. "That was really a surprise. That gives me hope that there's really something here, but there's a lot more work to be done."

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