The common theme that arises from central nervous system (CNS) injury research is how basic studies can inform the development of therapies. In each of the primary CNS injuries—spinal cord injury, stroke, and brain tumors—treatments are lacking, in large part because of the complexity of the underlying processes.
Research has therefore mainly focused on unraveling the processes of cell death, nerve regeneration, and tumor genesis, with the ever-present goal of translating that knowledge into molecularly targeted treatments that prevent or repair nervous system damage.
In one of the year’s biggest headline grabbers, a paralyzed man controlled a computer using thoughts. This advance is the culmination of decades of basic research on the brain’s motor control center (also discussed in the Neuroethics section, page 36). A pilot study on this one patient, reported in Nature by John Donoghue of Brown University and a Harvard-based team of collaborators, proved the concept that a brain-computer interface can record neural activity from a person’s primary motor cortex and translate it into specific actions on external devices.1
|Brain-computer interface: In a pilot study, a brain-computer interface allowed a single patient with paralysis to operate a computer using only his thoughts. Paired with a muscle stimulator system, such technology may one day allow people who are paralyzed to move their limbs again. (Illustration courtesy of Cyberkinetics Neurotechnology Systems, Inc.)|
The man in the study, paralyzed from the neck down in a spinal cord injury three years ago, was able to open e-mail messages, operate a television and light switches, open and close a prosthetic hand, and perform rudimentary actions with a multijointed arm. The work represents an early step toward thought-powered robotics, which are envisioned as tools to help restore some degree of independence to people paralyzed by central nervous system damage. The authors were careful to note that the technology requires further refinement before it can be practically applied beyond a research setting.
Spinal Cord Repair
The many aspects of spinal cord injury require correspondingly diverse approaches to treatment, and researchers are just beginning to combine different therapeutic strategies in animal studies. Researchers continue to wrestle with fundamental difficulties in coaxing axons, the nerve fibers that transmit brain signals from cell to cell, to regenerate. The challenges include figuring out how to induce severed nerve fibers to regrow in the right directions and reconnect to the right targets to reestablish neuronal communication.
Problems that compound these difficulties include the physical gap produced by a break or crush injury to the spinal cord, the development of an impenetrable “glial scar” at the injury site, the presence of inhibitory molecules in the scar and spinal cord that block regrowth of axons (communication cables), and the complicated dynamics of guiding axons. Research is focusing on identifying and testing substances that might counteract these built-in inhibitors of axonal growth.
One substance being tested is a naturally occurring bacterial enzyme, chondroitinase ABC, which has been shown in previous research to stop inhibitory molecules called proteoglycans from forming in the glial scar. James Massey and colleagues at the University of Louisville reported in the Journal of Neuroscience that injecting chondroitinase into the brain stem of rats with cervical spinal injuries promoted nerve sprouting at the injury site, confirming earlier reports.2
Researchers at Johns Hopkins and the University of Michigan, led by Ronald Schnaar and reporting in Proceedings of the National Academy of Sciences, also found that chondroitinase ABC induced axon growth in an animal model of spinal cord injury. They also discovered a second bacterial enzyme, sialidase, which appears to double axonal growth in rats with nerve injuries.3
In addition to helping overcome the innate inhibitors of axon regrowth, researchers are working to identify the basic biological processes that drive axons to grow and connect properly. Three research groups reported preliminary results in this area in 2006.
Yuqin Yin and Larry Benowitz of Children’s Hospital Boston reported in Nature Neuroscience that they had discovered a naturally occurring growth factor, oncomodulin, that increased nerve regeneration five- to seven-fold when given to rats with injuries to the optic nerve.4 From the Salk Institute laboratory of Samuel Pfaff comes evidence, reported in Neuron, that a different type of growth factor, fibroblast growth factor, actively lures growing axons to reconnect with the right cell targets in muscles.5 And researchers at Yale led by Paul Forscher wrote in Nature Cell Biology that they identified novel functions for a molecular “motor” protein, myosin-II, that helps direct nerve growth at the tip of the axon.6 These reports shed new light on how processes involved in nervous system development might be harnessed for regenerating nerves after an injury.
Elsewhere, a research group led by Jerry Silver at Case Western Reserve University used chondroitinase ABC in combination with a “neural bridge” to facilitate axon regrowth across a spinal cord injury in a rat model. The team first transplanted a segment of the animal’s sciatic nerve into the gap created by the injury. This transplant formed a bridge across which newly sprouting axons could grow. Next, they delivered a steady dose of chondroitinase ABC enzyme via an implanted pump to promote sprouting and prevent further scarring at the injury site. These rats had markedly improved mobility compared to rats that underwent the same procedure but received an inactive saline solution rather than chondroitinase ABC. The latter rats showed no new axon growth or any improvement in movement. The results appeared in the Journal of Neuroscience.7
Researchers at Johns Hopkins University led by Douglas Kerr took a similar approach. They transplanted motor neurons into animals with spinal cord injury, then treated the area with a cocktail of chemicals designed to overcome signals that inhibit axon growth. Next they infused a nerve growth factor that guides axons to make the right connections. The result, reported in Annals of Neurology, was a partial restoration of function in the paralyzed animals.8
These preliminary reports in animal models of spinal cord injury are helping to define potential approaches that one day may be used in humans.
The number of new strokes each year has decreased dramatically during the past few decades, thanks to drugs that lower the two major risk factors: hypertension and cholesterol.
For those who experience a stroke from a blood clot (ischemic stroke), tissue plasminogen activator (tPA), if given within three hours of stroke onset, helps to dissolve the clot and may be effective in minimizing damage. But acute treatment with tPA is grossly underutilized in current practice, in part because so few eligible patients reach a stroke unit within the requisite three hours of symptom onset.
Data from a statewide stroke registry in Minnesota found that only 2 percent of patients with blood clots received tPA. Among patients who did not receive tPA, 41 percent arrived at the hospital beyond the three-hour therapeutic window and another 38 percent could not specify a time of symptom onset. Mathew Reeves of Michigan State University led the Minnesota registry study, which was reported in Neurology.9
These studies demonstrate the need for development of therapies that can effectively improve brain function and recovery even if they are not administered within three hours of ischemic stroke onset.Initial steps on this front come from clinical trial results of a neuroprotective drug designed to limit brain damage following acute ischemic stroke. Although neuroprotective drugs have been in development for two decades, this compound, NXY-059, is the first drug candidate to be developed in accordance with new expert standards designed to advance clinical stroke research. When administered within six hours of acute ischemic stroke onset, the drug reduced the rate of disability at 90 days after the stroke. However, no improvements were observed in neurological function, according to Warren Wasiewski of the Western Infirmary in Glasgow, Scotland, the principal investigator for the multisite study, which was reported in the New England Journal of Medicine.10 The emphasis is still on the development of “clot-busting” agents with a longer time window.
Deadly brain tumors called gliomas remain resistant to therapies, and patients usually die within two years of diagnosis. Scientists still have few leads about how these tumors arise and how to prevent or treat them.
Basic neuroscience investigations into glioma genesis have focused heavily on the connection between stem cells and brain tumor cells, expanding earlier research on whether stem cells may produce substances that promote cancer growth. Jeremy Rich and colleagues at Duke University wrote in Cancer Research about a specific type of glioma cell, which they called a “stem-cell-like glioma cancer cell” because of its shared characteristics with normal stem cells.11
The researchers examined how this type of glioma cell fuels tumor growth. They found that the cells produce large amounts of a natural substance called vascular endothelial growth factor (VEGF), which promotes formation of blood vessels that carry oxygen and nutrients to the glioma cells to foster their growth and proliferation.
Meanwhile, work by scientists at the National Institute of Neurological Disorders and Stroke and the National Cancer Institute, led by Howard Fine and reported in Cancer Cell, implicates a growth factor called stem cell factor (SCF) as a key contributor to tumor growth.12 Like VEGF, SCF also seems to drive cancer progression by setting up a local environment supportive of blood vessel formation. An important therapeutic strategy is to find ways to starve tumors of blood and oxygen by blocking blood vessel growth around a tumor.
Researchers also are investigating potential therapeutic roles for stem cells in treating glioma. As a team led by Arturo Alvarez-Buylla at the University of California, San Francisco, wrote in Neuron, a signaling molecule that regulates brain cell development in adults causes invasive tumorlike growths in mice when the molecule is abnormally stimulated, while removing the stimulation causes the tumors to regress.13 This suggests a possible treatment strategy of inhibiting malignant gliomas by blocking the signaling pathway.