For release: Tuesday, May 3, 2011
Research shows that the chemotherapy drug taxol (also called paclitaxel) could help improve recovery from spinal cord injuries. Writing in Science,* a team led by Frank Bradke, Ph.D., of the Max Planck Institute of Neurobiology in Martinsried, Germany reports that taxol helps repair spinal connections and improves walking in rats with spinal cord damage.
Dr. Bradke and his team found that the drug acts on two distinct processes that occur after a spinal cord injury. Such injuries can sever axons – the long branches of neurons that run up and down the spinal cord like electrical cables. Later, even if the axons are capable of regenerating, they are often blocked by scar tissue that forms around the injury. Taxol appears to aid recovery by directly stimulating axon growth and by reducing the formation of scar tissue.
Taxol is approved for treating several types of cancer, and is known to stabilize structural proteins within cells called microtubules. Inside our cells, microtubules act like a system of support beams, and can assemble and rearrange themselves, allowing a cell to change shape, grow, or even split in two. By stabilizing microtubule assembly inside cancer cells, taxol prevents the cells from dividing.
Inside a neuron, an orderly array of microtubules runs the length of the axon. In previous work, Dr. Bradke and others have found that when a spinal axon is severed, this microtubule network collapses and the axon dies back. By shoring up microtubules, taxol appears to stabilize axons near the site of injury and improve their regeneration.
Prior research also suggested that taxol might reduce scarring after a spinal cord injury. The scarring occurs when cells called astrocytes converge on the injury, isolating it from surrounding tissue. Meanwhile, a dense meshwork of proteins (or extracellular matrix) forms around the injury, further sealing it off and interfering with regeneration. Animal studies have suggested that taxol can quell these kinds of reactions in other tissues – such as renal interstitial fibrosis, a type of scarring associated with kidney failure. Dr. Bradke theorized that the drug might have similar effects in the spinal cord.
He and his team used a miniature pump and catheter to deliver taxol directly to the rat spinal cord immediately after injury. The rats had reduced scarring after one week of treatment, and enhanced spinal axon regeneration after four weeks. After six weeks, the rats showed significant improvements in walking. In cell culture experiments, taxol also interfered with the effects of TGF-beta, a secreted protein known to promote scarring.
"The ability of taxol to support axon regeneration has been recognized for some time. The work by Dr. Bradke and his colleagues suggests it also inhibits the scarring process, which has been a major challenge in spinal cord injury research," said Naomi Kleitman, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS).
Like most chemotherapeutic drugs, taxol has toxic side effects. For some cancer patients, it can cause nerve damage and debilitating nerve pain, which may be related to its effects on the axon microtubule network. But for patients with spinal cord injury, it could be effective at a very low, non-toxic dose, Dr. Bradke said. In the injured rats, it was effective at a dose 100 to 1000 times lower than the doses used in chemotherapy, with no apparent side effects. Pumping the drug directly into the spinal cord probably helped limit its toxicity. For cancer, the drug is typically delivered by intravenous injection.
These factors could accelerate pilot trials of taxol for spinal cord injury, but "we should take it slowly even if the prospect is exciting," Dr. Bradke said.
"It will be important to do more tests in the rat model involving different injury paradigms and other measures of functional recovery, and then move on to other animal models. This will give us a sense of how robust the effects of taxol are and whether we can translate them to humans."
The study was funded primarily by the Max Planck Society, with additional funding from NINDS, the Deutsche Forschungsgemeinschaft, the Human Frontiers Science Program and other organizations. Dr. Bradke's collaborators included John Bixby, Ph.D., and Vance Lemmon, Ph.D., at the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine; and Andres Hurtado, M.D., at the Kennedy Krieger Institute and the International Center for Spinal Cord Injury, Johns Hopkins University, Baltimore.
- By Daniel Stimson, Ph.D.
Image caption: Scar tissue in the injured rat spinal cord. Extracellular matrix (green) is surrounded by finger-like projections from astrocytes (red). Courtesy of Dr. Frank Bradke, Max Planck Institute.
*Hellal F et al. "Microtubule Stabilization Reduces Scarring and Causes Axon Regeneration after Spinal Cord Injury." Science, February 18, 2011, Vol. 331(6019), pp. 928-31.
Last Modified May 18, 2011