In a major step in spinal cord injury research, scientists at the University of California, San Diego School of Medicine have demonstrated that regenerating axons can be guided to their correct targets and re-form connections after spinal cord injury. Their findings will be published in the advance online edition of the journal Nature Neuroscience on August 2.

In the last few years, researchers have shown that the severed wires of the spinal cord, called axons, can be induced to regenerate into and beyond sites of experimental spinal cord injury. But a key question has been how these regenerating axons, on reaching the end of an injury site, can be guided to a correct cell target when faced with millions of potential targets. Further, can regenerating axons form functional, electrical connections called synapses?

“The ability to guide regenerating axons to a correct target after spinal cord injury has always been a point of crucial importance in contemplating translation of regeneration therapies to humans,” said senior author Mark Tuszynski, MD, PhD, professor of neurosciences and director of the Center for Neural Repair at UC San Diego, and neurologist at the Veterans Affairs San Diego Health System. “While our findings are very encouraging in this respect, they also highlight the complexity of restoring function in the injured spinal cord.”

The UC San Diego study looked at regenerating sensory axons in rat models of spinal cord injury. Sensory systems of the body send axons long, slender projections of the neuron into the spinal cord to convey information regarding touch, position, and pain. Many sensory axons are covered by an insulating myelin sheath which helps these impulses travel efficiently to the brain.

In certain spinal cord injuries, the axons are severed and the myelin sheath damaged. Loss of these systems results in an inability to feel or sense the body. The axons can no longer link to their targets in the brain, which blocks the electrical impulses from reaching the central nervous system.

The UC San Diego scientists showed that regenerating axons can be guided to correct targets using a type of chemical hormone called a growth factor. The team utilized a type of chemical hormone, a nervous system growth factor called neurotrophin-3 (NT-3), to guide regenerating sensory axons to the appropriate target and support synapse formation. Regeneration required two other treatments at the same time: placing a cell bridge in the spinal cord injury site to support axon growth, and a “conditioning” stimulus to the injured neuron that turned on regeneration genes for new growth.

When the growth factor was placed in the correct target as a guidance cue, axons regenerated into it and formed synapses. When the growth factor was placed in the wrong target, axons also followed the growth factor and grew into the wrong region.

Using high-resolution imaging systems, the scientists showed that regenerating axons guided to the correct cell formed synapses that were precisely on target. These axons contained rounded vesicles small packets at the end of the axon, packed with the chemical messengers needed to support electrical activity in the newly formed circuit.

Nonetheless, the connections were not electrically active. Additional study revealed the likely reason for this: the regenerating axons were not covered in myelin, the insulating material of the nervous system.

“Restoring axonal circuitry is complex, requiring several concurrent therapies to achieve axonal regeneration into and beyond a spinal cord lesion site,” said Tuszynski. “But, just as an electrical circuit needs insulation so it doesn’t short-circuit, it appears that these regenerating axons require restoration of the myelin sheath to ultimately restore function.” This will be the next step in the team’s research.

In earlier research (reported in PNAS April 6), the UC San Diego team achieved the first corticospinal motor axon regeneration by genetically engineering injured neurons to over-express receptors for another type of nervous system growth factor called brain-derived neurotrophic factor (BDNF). The growth factor was delivered to a brain lesion site in injured rats, where axons responded and regenerated into the injury site.

The lead author of the Nature Neuroscience study is Laura Taylor Alto of UCSD’s Department of Neurosciences. Additional contributors include Leif A. Havton of UCLA, and James M. Conner, Edmund R. Hollis II and Armin Blesch of UCSD Department of Neurosciences. Their work was supported by the National Institutes of Health, the Veterans Administration, the International Spinal Research Trust, Wings for Life, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Bernard and Anne Spitzer Charitable Trust.

University of California - San Diego

A common food additive that gives M&Ms and Gatorade their blue tint may offer promise for preventing the additional and serious secondary damage that immediately follows a traumatic injury to the spinal cord. In an article published online today in the Proceedings of the National Academy of Sciences, researchers report that the compound Brilliant Blue G (BBG) stops the cascade of molecular events that cause secondary damage to the spinal cord in the hours following a spinal cord injury, an injury known to expand the injured area in the spinal cord and permanently worsen the paralysis for patients.

This research builds on landmark laboratory findings first reported five years ago by researchers at the University of Rochester Medical Center. In the August 2004 cover story of Nature Medicine, scientists detailed how ATP, the vital energy source that keeps our body’s cells alive, quickly pours into the area surrounding a spinal cord injury shortly after it occurs, and paradoxically kills off what are otherwise healthy and uninjured cells.

This surprising discovery marked a milestone in establishing how secondary injury occurs in spinal cord patients. It also laid out a potential way to stop secondary spinal injury, by using oxidized ATP, a compound known to block ATP’s effects. Rats with damaged spinal cords who received an injection of oxidized ATP were shown to recover much of their limb function, to the point of being able to walk again, ambulating effectively if not gracefully.

Now, scientists detail the clearing of yet another hurdle in moving this research closer from bench to bedside by successfully identifying a compound that could be administered systemically to achieve the same benefit. Previously, the team needed to inject a compound directly into the injured spinal cord area to achieve its results.

“While we achieved great results when oxidized ATP was injected directly into the spinal cord, this method would not be practical for use with spinal cord-injured patients,” said lead researcher Maiken Nedergaard, M.D., D.M.Sc., professor of Neurosurgery and director of the Center for Translational Neuromedicine at the University of Rochester Medical Center. “First, no one wants to put a needle into a spinal cord that has just been severely injured, so we knew we needed to find another way to quickly deliver an agent that would stop ATP from killing healthy motor neurons. Second, the compound we initially used, oxidized ATP, cannot be injected into the bloodstream because of its dangerous side effects.”

Nedergaard cautions that while this body of work offers a promising new way of treating spinal cord injury, it is still years away from possible application in patients. In addition, any potential treatments would only be helpful to people who have just suffered a spinal cord injury, not for patients whose injury is more than a day old. Just as clot-busting agents can help patients who have had a stroke or heart attack who get to an emergency room within a few hours, so a compound that could stem the damage from ATP might help patients who have had a spinal cord injury and are treated immediately.

Too Much of a Good Thing

While ATP is usually considered to be helpful to our bodies after all, it’s the main source of energy for all of our body’s cells Nedergaard was the first to uncover its darker side in the spinal cord. Immediately after a spinal cord injury occurs, ATP surges to the damaged area, at levels hundreds of times higher than normal. It is this glut of ATP that over-stimulates neurons and causes them to die from metabolic stress.

Neurons in the spinal cord are so susceptible to ATP because of a molecule known as “the death receptor.” Scientists know that the receptor called P2X7 plays a role in regulating the deaths of immune cells such as macrophages, but in 2004, Nedergaard’s team discovered that P2X7 also is carried in abundance by neurons in the spinal cord. P2X7 allows ATP to latch onto motor neurons and send them the flood of signals that cause their deaths, worsening the spinal cord injury and resulting paralysis.

So the team set its sights on finding a compound that not only would prevent ATP from attaching to P2X7, but could be delivered intravenously. In a fluke, Nedergaard discovered that BBG, a known P2X7R antagonist, is both structurally and functionally equivalent to the commonly used FD&C blue dye No. 1. Approved by the Food and Drug Administration as a food additive in 1982, more than 1 million pounds of this dye are consumed yearly in the U.S.; each day, the average American ingests 16 mgs. of FD&C blue dye No. 1.

“Because BBG is so similar to this commonly used blue food dye, we felt that if it had the same potency in stopping the secondary injury as oxidized ATP, but with none of its side effects, then it might be great potential treatment for cord injury,” Nedergaard said.

The team was not disappointed. An intravenous injection of BBG proved to significantly reduce secondary injury in spinal cord-injured rats, who improved to the point of being able to walk, though with a limp. Rats that had not received the BBG solution never regained the ability to walk. There was one side effect: Rats who were injected with BBG temporarily had a blue tinge to their skin.

Nedergaard’s long-time collaborator on this and other projects, chair of the University of Rochester Department of Neurology Steven Goldman, M.D., Ph.D., adds, “We have no effective treatment now for patients who have an acute spinal cord injury. Our hope is that this work will lead to a practical, safe agent that can be given to patients shortly after injury, for the purpose of decreasing the secondary damage that we have to otherwise expect.”

Nedergaard and Goldman believe that further laboratory testing will be needed to test the safety of BBG and related agents before human clinical trials could begin. Nonetheless, the investigators are optimistic that with sufficient study, strategies like this could yield new treatments for acute spinal cord injuries within the next several years.

Other authors from the University of Rochester Medical Center include Weiguo Peng, Maria L. Cotrina, Xiaoning Han, Hongmei Yu, Lane Bekar, Livnat Blum, Takahiro Takano, and Guo-Feng Tia.

The research was supported by the New York State Spinal Cord Injury program, the Miriam and Sheldon Adelson Medical Research Foundation, and grants from the National Institutes of Health.

University of Rochester Medical Center

Multiple route bone marrow stem cell injections show promise to treat spinal cord injuryResearchers from DaVinci Biosciences, Costa Mesa, California, in collaboration with Hospital Luis Vernaza in Ecuador, have determined that injecting a patient’s own bone marrow-derived stem cells (autologous BMCs) directly into the spinal column using multiple routes can be an effective treatment for spinal cord injury (SCI) that returns some quality of life for SCI patients without serious adverse events.

Publishing in the current issue of Cell Transplantation (Vol. 17 No.12), the researchers reported on eight patients with SCI (four acute and four chronic) to whom they administered BMCs directly into the spinal column, spinal canal and intravenously for each patient and followed for two years using MRI imaging to assess morphological changes in the spinal cord.

“Our objective in this study was to demonstrate that multiple route administration of BMCs for SCI is safe and feasible,” said corresponding author Dr. Francisco Silva. “To date, we have administered BMCs into 52 patients with SCI and have had no tumor formations, no cases of infection or increased pain, and few instances of minor adverse events. We also found that patient quality of life improved.”

According to Dr. Silva, presently there is no cure or effective treatment for spinal cord injury, a disorder affecting millions globally. Tissue loss from the primary injury and the complexity of cell types required for functional recovery lead the list of considerations. Once more, to be considered successful, any treatment should ultimately help to improve patient quality of life and demonstrate functional improvements.

“Autologous stem cell transplantation of BMCs can promote the growth of blood vessels and, therefore, represent an alternative therapy,” said Dr. Silva.

Following primary trauma to the adult spinal cord there is evidence of hemorrhage and blood flow is attenuated, he explained. The disruption of blood flow leads to spinal cord infarction, the disruption of the blood-spinal cord injury barrier, swelling and the release of molecules influencing spinal cord perfusion and ischemia, a restriction in blood supply.

“BMCs are well known for their ability to grow blood vessels,” explained Dr. Silva. “This angiogenesis is necessary for wound healing and establishing a growth permissive environment. We hypothesized that improved blood flow and oxygen supply could contribute to functional improvements for SCI transplanted with autologous BMCs.”

In eight patients who received BMC transplants through various routes and followed for two years, the scientists reported several functional improvements, perhaps the most important of which was improved bladder control.

Finally, the researchers noted that one of their cases suffered a gunshot wound and that their study marked the first time a gunshot wound victim had received BMC transplants through multiple routes.

“It is important to note,” concluded Dr. Silva,” that all of our patients with acute injuries improved significantly with no signs of deterioration or impediment of presumed spontaneous recovery.”

According to Dr. Svitlana Garbuzova-Davis, a spinal cord researcher at the University of South Florida, the study highlights the value of using several different simultaneous routes for the administration of stem cells, as well as the benefit of the cells themselves.

“While it would be interesting to know the respective contribution of each route of administration, this study does appear to support the need to move to carry out double blind clinical trials of BMCs in SCI, especially if a non-invasive route could be used.”

Multiple route bone marrow stem cell injections show promise to treat spinal cord injuryCell Transplantation Center of Excellence for Aging and Brain Repair

A spinal cord injury often leads to permanent paralysis and loss of sensation below the site of the injury because the damaged nerve fibers can’t regenerate. The nerve fibers or axons have the capacity to grow again, but don’t because they’re blocked by scar tissue that develops around the injury.
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