In 2004, the first evidence that the common energy molecule ATP (adenosine triphosphate) was released into injured spinal cord tissue and induced cell death, was reported in laboratory animals. Significantly, rapid administration of inhibitors of the action of ATP, eliminated most of the damage, promoted healing and reestablished some function. The problem with this approach, was that it required direct injection of ATP inhibitors into the injured spinal cord.
ATP Activates P2X7 Receptor, Inflammation and Cell Death
ATP outside of cells serves as a signal molecule that binds to a cell surface receptor protein, P2X7 receptor. ATP binding to the P2X7 receptor forms an ion pore in sensitive cells and an influx of calcium ions triggers release of inflammatory cytokines and cell death. Activation of P2X7 receptors is also found in many degenerative diseases of the nervous system, including amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease.
Blood-Brain Barrier Blocks Drugs from Injured Tissue
Proteins, blood cells and most drugs cannot cross the lining of blood vessels and migrate into brain or spinal cord tissues. This lining, consisting of a layer of endothelial cells tightly connected by protein bridges and embedded in a matrix of proteins and polysaccharides (heparan sulfate proteoglycans), is called the blood-brain barrier (BBB).
Search for BBB-Penetrating ATP Inhibitor
As soon as research demonstrated that ATP inhibitors could block inflammation and progressive damage in injured spinal cords, the search began for inhibitors able to penetrate the BBB and block P2X7 receptor activation. One of the candidates tested was a common blue dye, Brilliant Blue G (BBG). BBG is non-toxic and binds strongly to proteins. Consequently, it is a food dye (FD&C Food Dye No. 1) and produces vivid blue colors at low concentrations. Intense staining of proteins has also made BBG, a.k.a. Coomasie Brilliant Blue, a favorite in research laboratories for staining proteins in gels used to separate proteins by molecular mass and charge, e.g. SDS-PAGE. Low toxicity and high penetration of the BBB made BBG a good candidate for animal trials of treatment of spinal cord injuries.
Blue Mice Recover from Spinal Cord Injuries
In a recent publication (reference below), a research group headed by Dr. Maiken Nedergaard at the University of Rochester, demonstrated that mice with spinal cord injuries recovered substantially if treated by intravenous administration of BBG. The only notable side effect of the treatment was that the skin and eyes of the mice became blue.
BBG as a Treatment for Spinal Cord Injuries
Development of BBG for immediate treatment of spinal cord injuries may help many avoid the paralysis of these injuries and greatly improve their quality of life. The research studies indicate that treatment with BBG, even two hours after injury, may greatly improve the outcome.
reference:
W. Penga, M. L. Cotrinaa, X Hana, H Yua, L. Bekara, L. Bluma, T. Takanoa, G.-F. Tiana, S. A. Goldman and M. Nedergaard. 2009. Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. PNAS 106:12489 –12493.
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