Brilliant blue for the spine

A blue dye found in Gatorade and Rocket Pops could play a protective role in the cellular mayhem that follows spinal cord injury. In rats, a close chemical cousin of the common food dye FD&C Blue No.1 appears to block a molecule that floods the injury site and kills nerve cells, a team reports in the July 28 Proceedings of the National Academy of Sciences.

Rats dosed with the dye — known as brilliant blue G — after injury showed greater improvement in motor skills than rats not receiving the dye. And assuming the food colorant’s low toxicity holds true for brilliant blue, the research suggests a new approach for treating spinal cord trauma in humans, injuries for which there are few therapies.

“It’s not a cure,” says neuroscientist Maiken Nedergaard of the University of Rochester Medical Center in Rochester, N.Y., who led the new study. “I don’t think that anything can cure this, but for the patient it could be a big improvement.”

The results are impressive and realistic, comments Lynne Weaver, a neuroscientist at the Robarts Research Institute in London, Canada. Weaver notes that the side effects of any new potential therapy must be considered, but “the principle is interesting.”

ATP, for adenosine triphosphate, is known as the energy currency of cells, and the molecule is used like a battery whenever cells need to get stuff done. But a few years ago Nedergaard and her colleagues reported that ATP has a darker side. It wreaks havoc when the central nervous system is injured, flooding the injury site and hitting a receptor that sits on some immune system cells. ATP binds to this receptor, called P2X7, resulting in a cascade of events that leads to cell death.

Cellular mayhem ensues for days after a spinal cord injury and can kill cells that may have survived the initial injury. Scientists think this delayed damage is what causes the lasting effects of these injuries, including paralysis. Swelling, due in part to ATP, and bleeding in the tight space of the spinal cord prevents cells from getting oxygen. Dying neurons spew toxic chemicals, and damaged cells leak calcium and sodium that can destroy other cells.

This cellular response is appropriate in other parts of the body, says Nedergaard, “but in the closed cavity of the spinal cord, it causes additional damage — there is no room to swell.”

Nedergaard and her colleagues had already established that blocking the P2X7 receptor could temper the damage from spinal cord trauma, but the team was looking for a nontoxic blocker. Brilliant blue stepped up. The dye has a structure similar to the known blocker, Nedergaard says. And the dye is very closely related to FD&C Blue No.1, which is considered very safe, with no toxicity in doses up to 12 milligrams per kilogram of body weight per day. The FDA approved the latter dye in 1928, and it commonly gives popsicle-eaters blue tongues and brightens various sports drinks.

The scientists first tested the brilliant blue’s toxicity, intravenously giving rats the dye in doses of either 10 or 50 mg/kg/day. While the 50 mg rats turned a little blue, this faded and neither regime seemed to have effects on physiology, such as blood pressure or blood pH.

Using a common study set-up that drops a heavy weight on a rat’s lower back, the scientists inflicted spinal cord injuries on the animals. Fifteen minutes later some of the rats received an IV dosed with the dye, and those rats got additional dye on days two and three after the injury. Initially, the severely injured rats couldn’t walk. But over the course of six weeks, the rats treated with the dye had improved locomotion and regained some bladder control, performing better on gait assessments than untreated rats, the scientists report.

It isn’t clear whether the dye could cross the blood-brain barrier into the spinal cord in a healthy rat, but that barrier is already broken in many spinal cord injuries, notes Nedergaard.

The research team is now exploring how effective the dye is when it is administered later, such as four hours after the injury. It looks like there is still a beneficial effect, Nedergaard says. While clinical use of brilliant blue is years off and would require studies in humans, it looks promising, Nedergaard says. “It could be you drink blue Gatorade on the way to the hospital,” she speculates.

Current treatments, including steroids, to prevent additional harm following a spinal cord injury can have big side effects, but they are considered worth tolerating, Weaver notes. And in the case of brilliant blue, even if the dye blocks ATP from binding to P2X7 elsewhere in the body, it is unlikely to be life threatening, she says.

Scientists are still trying to determine just how long the secondary cellular mayhem lasts and how quickly treatments must be administered, says Michael Beattie of the brain and spinal injury center at the University of California, San Francisco. Treating this secondary injury is a promising approach, he says, but he would like to see the study replicated.