Brilliant Blue G (BBG), the food additive that gives M&Ms and Gatorade their blue hue, offers promise for preventing the additional serious secondary damage immediately after a traumatic injury to the spinal cord.
An article1 published online in the Proceedings of the National Academy of Sciences, reports that the compound halts the chain of molecular events that cause the secondary damage. In the hours following a spinal cord injury, this secondary injury can enlarge the injured area of the spinal cord, permanently worsening paralysis in patients.
The research follows up on landmark laboratory findings2 reported in Nature Medicine in August 2004 by researchers at the University of Rochester Medical Center. The previous study explained how adenosine triphosphate (ATP), the energy source that fuels our body’s cells, rapidly pours into the area around a spinal cord injury shortly after it occurs, paradoxically killing off otherwise healthy and uninjured cells.
The discovery was a breakthrough in understanding secondary injury in spinal cord patients. Additionally, it laid out a possible method to stop secondary spinal injury, using oxidized ATP, a compound known to block ATP’s effects. It was shown that rats with damaged spinal cords receiving an injection of oxidized ATP recovered much of their limb function, even restoring ability to walk.
“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., 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.”
The current study details a compound that could be administered systemically to get the same benefits.
Dr. Nedergaard adds that although his work offers a promising new way of treating spinal cord injury, it is still years away from possible application in patients. Also, any treatments would only be helpful to people who have just suffered spinal cord injury, and not for patients whose injury is more than a day old.
Similar to how anti-clotting agents can help stroke or heart attack patients who get to an emergency room within a few hours, a compound that could stem the damage from ATP might help patients who have had a spinal cord injury and are treated immediately.
ATP, being the main source of energy for all of our body’s cells, is usually considered to be helpful to our bodies. Nedergaard was the first to uncover its not so helpful side in the spinal cord. Immediately after the occurrence of a spinal cord injury, ATP pours into the damaged area, at levels hundreds of times higher than normal. This flood of ATP over-stimulates neurons, causing them to die due to metabolic stress.
It is one specific molecule known as “the death receptor” that makes spinal cord neurons so vulnerable to ATP. It was known that the receptor, called P2X7, plays a role in regulating the deaths of immune cells such as macrophages3,4, but it wasn’t until 2004 that Nedergaard’s team discovered P2X7 is also carried in profusion by neurons in the spinal cord.
The team then set out to find a compound that would not only prevent ATP from attaching to the P2X7 receptors, but could be delivered intravenously. Nedergaard discovered that Brilliant Blue G, a known P2X7R antagonist, is equivalent both functionally and structurally to the commonly used FD&C blue dye No. 1. Approved as a food additive in 1982 by the FDA, more than 1 million pounds of this dye are consumed yearly in the U.S.; each day in fact, the average American ingests 16 mgs. of FD&C blue dye No. 1.
Brilliant Blue Rats
“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.
Their hunch played out. An intravenous injection of BBG proved to notably decrease secondary injury in spinal cord-injured rats, who improved to the point of being able to walk, though with a limp. The rats that had not received the BBG solution never regained the ability to walk. There was one temporary side effect; the rats that were injected with BBG had a blue tinge to their skin.
Further lab testing will be needed to ascertain the safety of BBG and similar agents before human clinical trials could begin, but investigators are optimistic that strategies like this could yield fresh treatment techniques for acute spinal cord injury within the next several years.
Weiguo Peng, Maria L. Cotrina, Xiaoning Han, Hongmei Yu, Lane Bekar, Livnat Blum, Takahiro Takano, Guo-Feng Tian, Steven A. Goldman, and Maiken Nedergaard Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury PNAS 2009 : 0902531106v1-pnas.0902531106.
Xiaohai Wang, Gregory Arcuino, Takahiro Takano, Jane Lin, Wei Guo Peng, Pinglan Wan, Pingjia Li, Qiwu Xu, Qing Song Liu, Steven A Goldman & Maiken Nedergaard P2X7 receptor inhibition improves recovery after spinal cord injury Nature Medicine 10, 821 - 827 (2004) doi:10.1038/nm1082
Sluyter R, Wiley JS (2003). “Extracellular adenosine 5'-triphosphate induces a loss of CD23 from human dendritic cells via activation of P2X7 receptors.”. Int. Immunol. 14 (12): 1415–21. doi:10.1093/intimm/dxf111
Wiley JS, Dao-Ung LP, Gu BJ, et al. (2002). “A loss-of-function polymorphic mutation in the cytolytic P2X7 receptor gene and chronic lymphocytic leukaemia: a molecular study.”. Lancet 359 (9312): 1114–9. doi:10.1016/S0140-6736(02)08156-4