How Keeping Axons Alive May Benefit Neuropathy Patients

Today's post from futurity.org (see link below) tries to explain the new findings regarding the death of nerve cells and nerve axons and how this may eventually lead to significantly better treatments for neuropathy patients. Another post here a few days ago (scroll down to May 3rd) announced the results of this research but as with many articles like this, many people might have found it difficult to follow. This article takes care to explain the science in words we can all understand and for that reason deserves a gold star from this blog. Worth a read - they may be onto something here.

Can saving axons keep nerves alive?
Washington University in St. Louis rightOriginal Study Posted by Caroline Arbanas-WUSTL on May 5, 2015

You are free to share this article under the Attribution 4.0 International license.

New research highlights how nerves—whether harmed by disease or traumatic injury—start to die.

The discovery unveils new targets for developing drugs to slow or halt peripheral neuropathies and devastating neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).

Peripheral neuropathy damages nerves in the body’s extremities and can cause unrelenting pain, stinging, burning, itching, and sensitivity to touch. The condition is commonly associated with diabetes or develops as a side effect of chemotherapy.

Nerve cells talk to each other by transmitting signals along communication cables called axons. Such signals underlie vital activities, such as thinking and memory, movement, and language.

As part of a study published in Science, the researchers showed they could prevent axons from dying, a finding that suggests therapies could be developed to counteract the withering away of nerve axons.

“We have uncovered new details that let us piece together a major pathway involved in axon degeneration,” says senior author Jeffrey Milbrandt, professor in, and head of, the genetics department at Washington University School of Medicine in St. Louis.

“This is an important step forward and helps to identify new therapeutic targets. That we were able to block axon degeneration in the lab also gives us hope that drugs could be developed to treat patients suffering from a variety of neurological conditions.” 

Energy supply

A common thread among many neurological disorders and traumatic nerve injuries is the degeneration of axons, which interrupts nerve signaling and prevents nerves from communicating with one another. Axon degeneration is thought to be an initiating event in many of these disorders. In fact, an unhealthy axon is known to trigger its own death, and researchers are keenly interested in understanding how this happens.

Working in cell cultures, fruit flies, and mice, Milbrandt and coauthor Aaron DiAntonio, professor of developmental biology, and their colleagues showed that a protein already known to be involved in axon degeneration acts like a switch to trigger axon degeneration after an injury.

Moreover, they found that this protein, once unleashed, causes a rapid decline in the energy supply within axons. Within minutes after the protein—called SARM1—is activated in neurons, a massive loss of nicotinamide adenine dinucleotide (NAD), a chemical central to a cell’s energy production, occurs within the axon.

“When a nerve is diseased or injured, SARM1 becomes more active, initiating a series of events that quickly causes an energetic catastrophe within the axon, and the axon undergoes self-destruction,” says first author Josiah Gerdts, an MD/PhD student in Milbrandt’s laboratory.
Keeping axons alive

Working in neurons in which SARM1 was activated, the researchers showed they could completely block axon degeneration and neuron cell death by supplementing the cells with a precursor to NAD, a chemical called nicotinamide riboside. The neurons were able to use nicotinamide riboside to keep the axons energized and healthy.

Nicotinamide riboside has been linked in animal studies to good health and longevity, but its benefits have not been shown in people. The researchers say much more research is needed to know whether the chemical could slow or halt axon degeneration in the body.

“We are encouraged by the findings and think that identifying a class of drugs that block SARM1 activity has therapeutic potential in neurological disorders,” Milbrandt says. “The molecular details this pathway provides give us a number of therapeutic avenues to attack.”

The National Institutes of Health (NIH) and Vertex Pharmaceuticals supported the work.

Source: Washington University in St. Louis 

http://www.futurity.org/nerves-neuropathy-axons-914382/

Gabapentin May Help Both Alcoholism And Neuropathy

Today's post from psypost.org (see link below) looks once again at gabapentin (neurontin) as a treatment for alcoholism. Why then does it feature on a neuropathy blog? Well alcoholism very frequently leads to nerve damage and neuropathic symptoms. Also gabapentin is a first-line treatment for neuropathy itself so any article looking at its efficiency is worth reading if that is what you have been prescribed. Now, gabapentin isn't universally trusted (see more articles to the right of this blog) and the possible side effects are enough to put many patients off but that is not the point here. The trial mentioned here concludes that it has a useful part to play in reducing alcohol dependence. That said, it was a small trial and you have to judge the outcomes on that as well. Certainly if you think you may have a drink problem and are already suffering from neuropathic symptoms it may be worth discussing the possibility of using gabapentin with your doctor.

Clinical trial indicates gabapentin is safe and effective for treating alcohol dependence
Scripps Research Institute / November 5, 2013

The generic drug gabapentin, which is already widely prescribed for epilepsy and some kinds of pain, appears to be safe and effective in the treatment of alcohol dependence. The finding comes from a 150-patient randomized, placebo-controlled, double blind clinical trial conducted by scientists at The Scripps Research Institute (TSRI).

“Gabapentin’s effect on drinking outcomes is at least as large or greater than those of existing FDA-approved treatments,” said Barbara J. Mason, Pearson Family Professor and co-director of the Pearson Center for Alcoholism and Addiction Research at TSRI, who led the new research. “Plus it’s the only medication shown to improve sleep and mood in people who are quitting or reducing their drinking, and it’s already widely used in primary care—that’s an appealing combination.”

The new research was published by the journal JAMA Internal Medicine on November 4, 2013.

Reducing Cravings, Depression, Sleeplessness

As a relatively safe, effective and well-tolerated drug, gabapentin has the potential to fill a large gap in the treatment of alcohol dependence. About eight and a half-million Americans are thought to have the condition, yet each year only a tiny fraction of them are prescribed one of the FDA-approved medications for alcohol dependence, due in part to the limitations of the existing drugs used for treatment.

The lack of treatment is striking in light of alcoholism’s enormous adverse impact on society. In addition to its other effects on the lives of individuals and their families, alcoholism promotes cancer, liver disease, strokes and heart attacks, as well as various other disabilities. Worldwide, about one out of 25 deaths is attributable to alcohol misuse.

In the new study, Mason and her colleagues randomly assigned each of 150 recently abstinent people with alcohol dependence to be treated with 900 mg or 1,800 mg of gabapentin or with a look-alike placebo. Over 12 weeks of treatment, the high-dose group ended up refraining from heavy drinking twice as often as the placebo group (45% vs. 23%) and entirely abstained four times as often (17% vs. 4%). The drug also significantly reduced the number of drinks consumed, as well as patient reports of cravings, depression and sleeplessness. None of the treated patients reported serious side effects.


Patients who received the lower, 900-mg dose of gabapentin showed intermediate benefits compared to the high-dose group, likely reflecting what clinicians call a “dose-response effect”—a good indication that the treatment really is working.

“I think that we can now have confidence in the pharmacological effect of this drug,” Mason said.

Filling a Gap

Two FDA-approved therapies for alcohol dependence have been around for decades. The first, disulfiram (Antabuse®), interferes with the body’s normal enzymatic breakdown of alcohol, making drinking an unpleasant experience. The second, naltrexone (ReVia®, Vivitrol®), blocks the opioid brain-cell receptors that help mediate the sense of reward during drinking.

Both treatments aim to blunt the pleasure-seeking motivation that helps initiate alcohol dependence. But they are relatively ineffective against the anxiety, depression, sleeplessness and other protracted withdrawal symptoms that help maintain alcoholism once it has been established. They are also, by design, somewhat unpleasant—which often discourages patients from using them.

A newer drug, acamprosate (Campral®), the only other medication approved by FDA for alcoholism treatment, does aim to normalize dysregulation in brain stress systems following acute withdrawal, similar to gabapentin. But it has shown only modest benefits on the whole in clinical trials, with no efficacy noted for mood or sleep.

Gabapentin has a favorable safety profile and appears to work by normalizing levels of the neurotransmitter GABA in an emotion-mediating part of the brain called the amygdala, thereby reducing anxiety and other stress-related withdrawal symptoms. A previous, proof-of-concept study of gabapentin by Mason’s group also found effects like those reported in this study in patients with cannabis dependence.

Gabapentin’s quieting effect on overactive brain areas has led to its approval by the FDA for treating epilepsy and neuropathic pain. It is also now widely prescribed “off-label” for other pain-related conditions, including migraines.

“I’m excited about the possibility that now more people will get treatment,” said Mason. “We really need to do more about treating alcohol dependence.”

http://www.psypost.org/2013/11/clinical-trial-indicates-gabapentin-is-safe-and-effective-for-treating-alcohol-dependence-21143