[Stitcher]

Researchers Fight War Against Brain's Enemies

By Melissa Healy
Los Angeles Times
http://www.nwaonline.net/articles/20...raininjury.txt

The human brain is a powerful and resilient organ. But it has many enemies and a dramatic vulnerability.

When under attack -- from ischemic stroke, head trauma or degenerative diseases -- a small cluster of affected brain cells basically commits suicide and, in so doing, releases toxins that kill off neighboring cells in droves. Neurons tumble like dominoes to their death in a process that can take hours (in a stroke or a head trauma) or years (in Alzheimer's or Parkinson's disease).

The physical symptoms of that cell death may vary from disease to disease, but the result is the same: disability that can make the simplest of human tasks difficult or impossible.

The medical profession has struggled to combat each of the brain's enemies separately and limit the damage and disability they wreak. But prevention is hard, and cures are elusive. It has been a war with few successes.

Like Seeking Holy Grail?

But what if there were a simple way to fortify human neurons against the brain's enemies? What if some safe, readily available compound, taken before or just after a stroke or injury or even long before a neurodegenerative disease takes hold, could protect the brain against insults and injuries?

This idea is called neuroprotection. Although the quest for it has a history of disappointment, some glimmers of hope are on the horizon.

"It's a little bit like the search for the Holy Grail," says Dr. Walter Koroshetz, deputy director of the National Institute of Neurological Disease and Stroke. "But I don't think there's anybody who doesn't believe eventually we're going to be able to do this. ... We need a success that we can build on."

To that end, the federal government launched a nationwide trial in March to investigate whether creatine -- a dietary supplement safely taken by bodybuilders at lower doses than those being tested -- can slow the die-off of neurons in early-stage Parkinson's disease.

A second promising neuroprotectant, the dietary supplement co-enzyme Q10, is set to enter clinical trials next year for early-stage Parkinson's diseaseas well.

This summer, the National Institute of Neurological Diseases and Stroke is expected to fund a national clinical trial to see if high doses of progesterone -- the hormone that surges during pregnancy but is present in all human brains -- can help disrupt the rapid death of brain cells in head trauma.

Scientists at the University of California, Los Angeles, are studying whether magnesium sulfate -- long used to stave off early labor and delivery -- can break the chain of destruction that leaves stroke patients disabled.

And a common antibiotic, minocycline, is being tested in humans as a way to slow Lou Gehrig's disease and Huntington's disease, a degenerative genetic disorder.

The science of neuroprotection is driven by a deepening understanding of how injury and disease damage the human brain.

Combat Injuries

In the wars in Afghanistan and Iraq, traumatic brain injury has become widespread, and the military's medical establishment has been poorly prepared. Almost 1,900 U.S. soldiers have been treated for traumatic brain injury. Pentagon estimates have suggested that as many as 28 percent of the 1.4 million troops that have served in Iraq and Afghanistan may have sustained mild brain injury from bomb blasts.

In March, the Pentagon announced it was spending $14 million to research blast injuries and help medics in the field better diagnose mild brain injury.

Meanwhile, 78 million baby boomers are reaching the peak years for stroke and degenerative brain diseases.

In the United States each year, 700,000 Americans suffer a stroke, and as many as 500,000 are diagnosed with a neurodegenerative disease (1.4 million suffer a traumatic brain injury). That has propelled the search for an agent that could limit or hold off disability across a range of illnesses.

All the substances currently under investigation have, in some form, long been in safe use and all have shown promise in protecting the brain against injury and disease.

Each of the compounds intervenes differently to disrupt the death of brain cells and subsequent disability. Some, such as creatine, pump up the metabolism of neurons and help them withstand the toxins released by dying cells.

"The biology of the neuroprotection has just exploded. It's just amazing," Koroshetz says. "There are so many different pathways people have identified that could potentially save brain cells from dying, it really piques your interest."

Moving With Caution

Researchers are wary. They have been here before and come up empty-handed.

"The graveyard of neuroprotectants is absolutely full. It's depressing," says Dr. David Wright, a professor of medicine at Emory University Medical School in Atlanta and a leader in testing progesterone for head injury.

But his hopes have been buoyed by studies suggesting that quickly elevating levels of progesterone, a steroid, may help save many with traumatic head injury and improve their outcomes.

In a three-year trial involving 100 such patients brought to Emory's Grady Memorial Hospital, 80 received a high dose of progesterone over 72 hours and 20 did not, receiving only standard care.

The study suggested that those receiving a rapid infusion of progesterone were 50 percent less likely to die. Among those who got the progesterone, there was less disability at the one-month mark than normally expected, considering the severity of their head injury.

"We think it's just shifting the whole curve," making all but the most severely injured patients better off, Wright says. "It way outdid what we were expecting."

Researchers caution against expecting what Koroshetz calls "the magic bullet" in a single study. It may be there, experts say, but it might be better to discover a compound's neuroprotective properties piecemeal, by looking at its effect on one kind of brain disease or injury at a time, or one group of patients at a time.

Then, with success, the possibilities of a neuroprotectant can be extended to other diseases and other patients.

"There are so many things going wrong" when the brain is under attack, says Dr. Robert M. Friedlander of Harvard University's Brigham and Women's Hospital, who has pioneered work on creatine as a neuroprotectant. "It's probably like plugging many holes in a cup: The more holes you plug, the better you do."