New research highlights how nerves – whether harmed by disease or traumatic injury – start to die, a discovery that unveils novel 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 the study, the researchers at Washington University School of Medicine in St Louis 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," said Dr senior author Jeffrey Milbrandt, the James S McDonnell professor and head of the department of genetics. "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."
A common thread among many neurological disorders and traumatic nerve injuries is the degeneration of axons, which interrupts nerve signalling 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 co-author Dr Aaron DiAntonio, the Alan A and Edith L Wolff 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 SARMI – 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.
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 said 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 said. "The molecular details this pathway provides give us a number of therapeutic avenues to attack."
Also a team of University of British Columbia researchers has made a significant discovery uncovering the cause of brain swelling after trauma to the head, which paves the way for a preventative drug treatment for severe brain damage following stroke, infection, head injury or cardiac arrest.
By turning off a single gene, scientists from the Djavad Mowafaghian Centre for Brain Health (DMCBH), a partnership of UBC and Vancouver Coastal Health, were able to successfully stop swelling in rodent brains.
"'known for years that sodium chloride accumulation in neurons is responsible for brain swelling, but now we know how it’s getting into cells, and we have a target to stop it," explains brain researcher Brian MacVicar, co-director of DMCBH with the Vancouver Coastal Health Research Institute and the study's principal investigator.
The team, including Terrance Snutch, director of translational neuroscience at the DMCBH, developed several novel technological approaches to identify the cascade of events that took place within individual brain cells as they swelled.
They then switched off the expression of different genes and were able to pinpoint a single protein – SLC26A11 – that acts as a channel for chloride to enter nerve cells. By turning off the chloride channel, the accumulation of fluid into the cells was halted, and nerve cells no longer died. "It was quite a surprising result, because we had few indications as to what this protein did in the brain," says Ravi Rungta, then a graduate student in the MacVicar lab and the paper's lead author.
Though the technique used by the researchers to block swelling and cell death is unlikely to work quickly enough to mitigate swelling in the case of real head trauma, the discovery has provided a target for drug development. "This discovery is significant because it gives us a specific target – now that we know what we’re shooting at, we just need the ammunition," says MacVicar. "That's what we're doing now: looking for drugs to inhibit the chloride channel."
[link url="http://news.wustl.edu/news/Pages/Major-pathway-identified-in-nerve-cell-death-offers-hope-for-therapies.aspx"]Washington School of Medicine in St Louis material[/link]
[link url="http://www.sciencemag.org/content/348/6233/453.abstract?sid=44e83d43-a9c0-4dc7-83d4-69c0efe161fe"]Science abstract[/link]
[link url="http://news.ubc.ca/2015/04/23/scientists-pinpoint-brain-swelling-mechanism-2/"]University of British Columbia material[/link]
[link url="http://www.cell.com/cell/abstract/S0092-8674(15)00316-5"]Cell article summary[/link]