Progesterone, for instance, may fortify the brain cells against degeneration caused by multiple sclerosis and has shown early promise as a protectant in stroke.
Animal studies suggest that creatine might be a neuroprotectant in stroke, traumatic brain injury and degenerative brain diseases such as Huntington's and Lou Gehrig's disease. And minocycline is seen as a drug that could slow the progress of Parkinson's disease and lessen the damage of stroke.
Magnesium sulfate failed in a recent clinical trial testing whether it could lessen disability after traumatic head injury. But in a trial published last year in the Journal of Thoracic and Cardiovascular Surgery, the chemical -- when administered during cardiopulmonary bypass surgery -- was shown to lessen the short-term memory loss and motor-control problems that patients frequently experience after such a cardiac procedure.
Each of these compounds intervenes differently to disrupt the chain of events that results in the death of brain cells and subsequent disability. Some, such as creatine, appear to pump up the metabolism of neurons and help them withstand the release of toxins from neighboring cells in their death throes.
Magnesium sulfate is thought to block the pathways by which neurotoxins infiltrate a cell and destroy it. Progesterone seems to do both and calms the destructive spasm of inflammation that is the brain's reaction to injury, stroke and many diseases.
"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."
Researchers are wary of hoping for too much. 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 who has been a leader in testing progesterone for head injury.
But his hopes have been buoyed by early studies suggesting that quickly elevating levels of progesterone, a steroid present in the brains of both men and women, 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 standard care only.
The study suggested that those receiving a rapid infusion of progesterone were 50% less likely to die. And among those who got the progesterone, there was less disability at the one-month mark than would normally be 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."
Marcus Baskett of Commerce, Ga., was one of those patients. A passenger in a head-on automobile collision just three weeks shy of his high school graduation, Baskett was evacuated by helicopter to Emory and received the progesterone infusion upon his arrival. In addition to broken bones, early tests of his brain function suggested massive and disabling head injury, and he spent almost three weeks in a coma.
But seven weeks after his April 2004 injury, Baskett was released from the hospital with lingering physical injuries but little evidence of the severe trauma to his brain. Three years later, a 21-year-old Baskett keeps up a rapid-fire conversation and lives close to his parents' home but independently, keeping track of appointments and birthdays on a cellphone scheduler.
"I wouldn't have believed that a woman's hormone drug would help my body and brain in a situation like that," Baskett says. "I'm back almost 100%, and I don't think I'd be here if it weren't for that drug."
Piecing together therapies
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.
As that research progresses, researchers hope that cocktails of neuroprotectant drugs may work on different pathways, or on different stages of disease or injury, to slow, stop or disrupt the damage they wreak on the brain.
"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 much of the 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."
And, doctors say, finding a neuroprotectant or a cocktail of neuroprotectants that work for many kinds of brain injury will take a bit of luck as well.
"I'm not trying to be pessimistic, just realistic," says Dr. Marc Mayberg, director of the Swedish Neuroscience Institute at the Swedish Medical Center in Seattle. "I think maybe there'll be a lucky break, the discovery of a very safe, easily administered neuroprotectant that will work in one condition, and people will start using it in other conditions and find it works as well."