St. Louis, Aug. 18, 1997 -- Molecules the shape of soccer balls shield nerve cells from many different types of damage, a new study finds. These buckyballs also delay symptoms and death in a mouse model of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease).
The work, published in the Aug. 19 Proceedings of the National Academy of Sciences, suggests that buckyballs might lessen the aftereffects of stroke, head trauma and spinal cord injury, according to Laura L. Dugan, M.D., lead author. Perhaps they also could be tested against Alzheimer's, Down syndrome and other neurodegenerative diseases, she says.
"These molecules protect nerve cells from a much wider range of harmful events than any other compounds we've tested," says Dugan, an assistant professor of neurology and medicine at Washington University School of Medicine in St. Louis. "And to our knowledge, this is the first demonstration that buckyballs can act as neuroprotective drugs in living animals."
Buckyballs--buckminsterfullerenes--are hollow spheres of 60 carbon atoms. Their architecture resembles that of R. Buckminster Fuller's geodesic domes. Because of their unique chemical structure, they can mop up huge quantities of highly reactive chemicals called free radicals.
Unmodified buckyballs are useless for medical research because they can dissolve only in harmful organic solvents, such as benzene. But Tien-Sung (Tom) Lin, Ph.D., a professor of chemistry at Washington University, suggested a way to make buckyballs water-soluble and biologically useful. In collaboration with Lin, Tien-Yau Luh, Ph.D., a chemistry professor at National Taiwan University, added side chains to the molecules. Buckyballs with carboxyl side chains--one carbon, two oxygens and one hydrogen--were completely water-soluble, Luh determined.
In Dugan's experiments, the modified buckyballs shielded cultured neurons during several harmful treatments that are known to increase free-radical production. For example, they protected against damage from chemicals that mimic glutamate, a neurotransmitter that kills brain cells after head injury, stroke or cardiac arrest. They also blocked the disintegration of nerve cells deprived of oxygen and glucose, the initial event in stroke.
Moreover, they prevented the programmed cell death that follows serum removal or exposure to amyloid peptide, a culprit in Alzheimer's disease. A cascade of cellular signals orchestrates this cellular suicide, and one of these signals is a free radical.
"Our working hypothesis is that the buckyballs act as generalized radical scavengers that prevent oxidative damage to cell membranes," Dugan says. "They also may interrupt the cell-suicide chain of commands."
To determine whether buckyballs can protect living animals, Dugan and colleagues studied genetically altered mice. The animals carried a human gene for an inherited form of ALS. The gene codes for one of the enzymes that normally rid cells of toxic superoxide radicals.
The nerves of these mice usually start to degenerate at eight weeks, and hind limb paralysis begins around week 15, two or three weeks before the animals die. But when the genetically altered mice received modified buckyballs through an abdominal pump, they developed hind-limb symptoms 10 days later than normal and lived an extra eight days.
"So their symptom-free life increased by up to 15 percent, and this added time was nearly half as long as the symptomatic period," Dugan says. "That makes us believe that, with better delivery systems, modified buckyballs eventually could be as protective in living animals and humans as in our cell-culture models."
The research was supported by grants from the National Institute of Neurological Disorders and Stroke, Hoffmann-La Roche Inc. and the National Science Council of Taiwan.
Journal
Proceedings of the National Academy of Sciences