Cautious Optimism for New Brain Drugs

Alzheimer's and multiple sclerosis among neurological diseases targeted by new drug class

/ Author:  / Reviewed by: Robert Carlson, M.D

When scientists discover a new type of drug that "promises" to become a "wonder" drug for all sorts of maladies, caution is a better route than joy and hope.

After all, thousands of drugs may show hopeful results in every creature from mice to monkeys but then fall flat in human clinical trials. That said, it's difficult for scientists not to be excited when they come across an entirely new type of drug that performs well in experiments.

Such a group of possible pharmaceuticals have recently been developed at Northwestern University's Feinberg School of Medicine as researchers explore a class of drugs that targets inflammation in the brain. Because brain inflammation is linked to several debilitating diseases that currently have no cure, the drugs' use could have far-reaching implications if it works in humans.

In fact, in a paper just published in the Journal of Neuroscience, where the scientists report on their research with these new drugs, lead researcher Adam D. Bachstetter, of the Sanders-Brown Center on Aging at the University of Kentucky at Lexington, and his colleagues say that these drugs may one day be able to treat Alzheimer's, multiple sclerosis (MS) and traumatic brain injury.

Most of the studies done on these drugs, currently called MW151 and MW189, have been conducted on mice, but a biotech company has recently completed the first human Phase 1 clinical trial for the drug. That means licensing and manufacturing of the drug could be almost a decade away, but the researchers are optimistic that the drug has made it to the first round of testing in humans.

How the Drugs Work

MW151 and MW189 come at conditions like Alzheimer's and multiple sclerosis in a different way than previous or even currently researched drugs do. With Alzheimer's, for example, much of the research is focusing on ways to prevent the development of amyloid plaques in the brain that are a hallmark of the disease.

Yet MW151 and MW189 aim instead to reduce inflammation in the brain. Alzheimer's, multiple sclerosis, traumatic brain injury, stroke and other neurological diseases all share brain inflammation as a primary characteristic that promotes the deterioration of the neurological system in a person.

Scientists believe that one factor contributing to brain inflammation and overall neurological damage is an overproduction of a group of brain proteins called proinflammatory cytokines. When numbers of these proteins overwhelm the brain, the brain's synapses - the connections that carry information from point A to point B - start misfiring.

Imagine your computer suddenly gets a number of viruses at once. They throw the various programs into chaos, and the hard drive starts sending bad information or commands to different programs. Eventually, the computer just crashes, and many of the files become so corrupted that they cannot be repaired.

In a sense, that's what happens to a human brain when it's flooded by these cytokines and throw the system into disarray. Instead of files becoming corrupt, the brain's neurons die, and damage occurs to two of the most important parts of the brain dealing with higher-level cognitive function: the cortex and the hippocampus. This damage is what leads to problems with memory, judgment and decision making.

"In Alzheimer's disease, many people now view the progression from mild cognitive impairment to full-blown Alzheimer's as an indication of malfunctioning synapses, the pathways that allow neurons to talk to each other," said D. Martin Watterson, a professor of molecular pharmacology and biological chemistry at the Feinberg School, where MW151 and MW189 were developed. "And high levels of proinflammatory cytokines can contribute to synaptic malfunction."

Because this harmful cytokine-flood plays a part in different conditions - including Alzheimer's, Parkinson's, multiple sclerosis, types of dementia and long-term brain injury - a single drug that prevents those cytokines from overproducing in the first place may be able to be used to treat a broad range of neurological diseases.

Animal Trials with the Drugs

A series of experiments with mice have investigated the drug's effectiveness in addressing Alzheimer's disease, multiple sclerosis and traumatic brain injury.

In one study, mice were genetically bred to develop Alzheimer's and then given MW151 three times a week starting when the mice were six months old. Six months is about the age when the cytokines that lead to inflammation start increasing in a mouse's brain. In humans, the beginning of cytokine overproduction is the point where a person might start to experience mild cognitive problems.

Five months later, when enough time had passed that the development of Alzheimer's should have been in full swing in the mice's brains, the scientists measured the levels of cytokines in the mice who received the drug. Instead of overwhelming numbers of them, the researchers found that the mice's cytokine levels were normal and their brain synapses were firing just as they should be. The mice who did not receive the drug still had exceptionally high levels of cytokines and improperly working synapses.

"The drug protected against the damage associated with learning and memory impairment," said Linda Van Eldik, a senior author in the study and the director of the Sanders-Brown Center on Aging. "Giving this drug before Alzheimer's memory changes are at a late stage may be a promising future approach to therapy."

Mice bred to develop multiple sclerosis and given MW151 showed similar success. With MS, the cytokines strip the insulating coverings of nerve cells that send information down the spinal cord, preventing the messages from being properly conveyed. The mice who received oral administration of MW151 still developed MS, but their symptoms were less severe than the mice who did not receive MW151.

The researchers working on that experiment were pleased to see that the disease was slowed down in the mice taking MW151 and have now been working on a trial to see if they can prevent MS relapses altogether in the mice.

Traumatic brain injury involves an overproduction of cytokines as well, this time created by a type of cell in the brain called glial cells. Glial cells normally support and protect the brain's neurons by holding them in place, providing them with oxygen and nutrients, protecting one neuron from another and destroying any dead neurons or invading germs.

But after the brain sustains significant trauma, the glial cells go into overdrive and produce proinflammatory cytokines that can eventually lead to cognitive problems and even epilepsy. Similar mechanisms in the brain can happen following a stroke, which also causes brain inflammation and can lead to epilepsy or other cognitive issues.

The researcher who focused on MW151's possible impact on traumatic brain injury in mice was Mark Wainright, MD, a professor of pediatric neurology at Feinberg and a doctor at the Ann & Robert H. Lurie Children's Hospital of Chicago. He gave the mice MW151 between three and six hours after they experienced a traumatic brain injury. Those who received the drug did not have their glial cells activated to overproduce the cytokines, so no cytokine flood leading to inflammation occurred.

"If you took a drug like this early on after traumatic brain injury or a even a stroke, you could possibly prevent the long-term complications of that injury including the risk of seizures, cognitive impairment and, perhaps, mental health issues," Dr. Wainwright said. In fact, Dr. Wainwright did conduct a separate study in which animals receiving MW151 after a traumatic brain injury had a reduced risk of epileptic seizures.

Proceeding with Caution

However, there is good reason for caution regarding the future of these drugs, according to Barry D. Jordan, MD, MPH, a neurologist and the director of the Brain Injury Program and of Memory Evaluation and Treatment Service at Burke Rehabilitation Hospital in White Plains, New York.

"Inflammation plays a role in all of these disorders, but the thing that's important is that inflammation can be good or it can be bad, and you've got to be careful to make sure that you're attacking the bad inflammation and not the good inflammation," Dr. Jordan said.

Given that these new experimental drugs are aiming to prevent or reduce inflammation, there is always the risk that too much of a good thing becomes a bad thing.

"Inflammation also plays a role in recovery," he said. "A good analogy is that if you cut yourself, inflammation is what helps you heal. You want to make sure that when you give an anti-inflammatory, you don't also block the good inflammation."

Further research is also necessary to determine whether drugs like MW151 and MW189 can necessarily stop or prevent a disease rather than simply slow its advance.

"It might slow down the damage, but whether it actually it is a disease-modifying drug, I'm not sure," Dr. Jordan said. "That's the question I have: is it going to treat the symptoms or is it going to be a disease-modifier?"

In all the experiments described in this study, the researchers determined that the timing of giving the drug was important to how well the mice responded. The drug needed to be given before the cytokines began overproducing and caused the initial inflammation. As further animal trials continue and the results of phase 1 human trials are published, researchers will learn whether the promise of this new class of drugs bears out and becomes a new kind of treatment to attack a number of currently incurable neurological diseases.

This research was supported by the American Health Assistance Foundation, an Alzheimer's Association Zenith award, the Kleberg Foundation and a couple grants from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke and the National Institutes of Health.

Reviewed by: 
Review Date: 
July 25, 2012