Zinc chelation: A better way to regenerate the optic nerve?

optic nerve zinc chelation

For more than two decades, researchers have tried to regenerate the injured optic nerve using different growth factors and/or agents that overcome natural growth inhibition. They’ve had partial success, sometimes even restoring rudimentary elements of vision in mouse models.

But at best, these methods get only about 1 percent of the injured nerve fibers to regenerate and reconnect the retina to the brain. That’s because most of the damaged cells, known as retinal ganglion cells (RGCs), eventually die, says Larry Benowitz, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

Benowitz and colleagues now show a surprising new approach that gets RGCs to live longer and regenerate robustly: using chelating agents to bind up zinc that’s released as a result of the injury.

These studies, too, were done in mice. If the findings hold up in human studies, they could spell hope for people with optic nerve injury due to trauma, glaucoma or other causes, and possibly even spinal cord injury.

A spike in zinc

Growth factors and survival factors don’t really stop the cell death process. If you deliver zinc chelators continuously at the right dosage, you might have half of the retinal ganglion cells surviving. Until now, what actually kills RGCs after optic nerve injury hadn’t been known. “At least 200 studies, including some done here, have tried to understand what makes these cells die,” Benowitz says. “And even if the cells survive, they usually cannot regrow their connections.”

It was Benowitz’s colleague, Paul Rosenberg, MD, PhD, who suggested looking at zinc in the retina. He had already been studying the role of zinc in the death of nervous system cells and knew that in many neurons, zinc is packaged together with the neurotransmitters used to communicate with other cells. The Rosenberg and Benowitz labs began collaborating in 2010, led by Yiqing Li, MD, PhD.

Zinc release is normally tightly controlled, because high levels are toxic to cells. But within an hour after injury to the optic nerve, the researchers watched zinc spike — surprisingly, not in the damaged RGCs themselves but in cells that talk to them, interneurons known as amacrine cells. Two or three days later, the zinc transferred to the RGCs — and only then did the cells begin to die.

A window of treatment opportunity?

This time lag offers a potential window for intervention. The researchers observed robust cell survival and axon regeneration even if treatment was delayed for as much as five days. Regeneration was further enhanced when chelators were combined with deletion of the pten gene to decrease natural growth inhibition.

optic nerve injury zinc
BLOCKING ZINC STIMULATES OPTIC NERVE REGENERATION: Top row: Cross-sections through the retina show very little free zinc (Zn2+; purple staining) in normal mice. But within an hour after optic nerve injury (right), zinc begins to accumulate in the retinal layer where amacrine cells connect with the retinal ganglion cells (RGCs). Over the next two days, the zinc transfers to the RGCs themselves, and these neurons die and cannot regenerate their damaged axons.  Second row: Treatment with chelating compounds allows many damaged RGCs to survive for months after the optic nerve is injured. The retina treated with chelation (far right) is shown two weeks after injury. Bottom two panels show the optic nerve two weeks after injury. Without treatment, no axons regenerate beyond the injury site (asterisk), whereas zinc chelation leads to extensive regeneration.

Zinc chelators already exist and could potentially be given systemically or though direct injection into the eye after an optic nerve inury. The team hopes to get further funding to develop a slow-release formulation that would chelate zinc over a period of time. This could potentially allow patients to receive just a single injection.

“When we used zinc chelators, we enabled about 40 percent of the injured cells to survive for months and possibly indefinitely,” says Benowitz. “Growth factors and survival factors only have a transient effect; they don’t really stop the cell death process. If you hit the right dosage and deliver zinc chelators continuously, you might have half of the retinal ganglion cells surviving.”

Zinc: The new calcium?

zinc chelation optic nerve injury
Cells normally control zinc levels tightly. (Jurii/Wikimedia Commons)

Benowitz, Rosenberg and Li are also interested in exploring how zinc causes cell death and blocks regeneration. “We think more ideas for new therapeutic approaches could come out of these investigations,” says Rosenberg.

While this is the first study to demonstrate the role of zinc in optic nerve injury, zinc has also been shown to play a role in stroke injury and has been implicated in Alzheimer’s disease and amyotrophic lateral sclerosis.

“Very little is known about the role of zinc in the healthy nervous system or its role in brain injury, although through the work of many groups around the world we are beginning to appreciate its significance,” says Rosenberg. “Everyone has thought of calcium as the master regulator in health and disease. We think zinc will come to share that role in the 21st century.”

Get more information on licensing this discovery or contact connie.caron@childrens.harvard.edu for details. For more on neuroscience at Boston Children’s, visit the Kirby Center.