Migraine drug activates transplanted eyes in tadpoles

Blind tadpoles with eyes grafted onto their tails were able to process visual information after being treated with a small molecule neurotransmitter drug. (Credit: Allen Discovery Center at Tufts University.)

What can blind tadpoles teach us about improving organ transplants, correcting birth defects and curing cancer? A lot, it turns out. That’s what scientists at the Allen Discovery Center at Tufts University discovered when they grafted eyes onto the tails of tadpoles, treated them with an FDA-approved migraine drug, then watched as the creatures regained some of their vision—and adapted to the odd position of their new eyes.

The researchers set out to promote “innervation,” the process by which the body supplies nerves to organs and tissues. They discovered that the migraine drug, called Zomig (zolmitripan) and sold as a nasal spray by AstraZeneca, produced a significant increase in innervation. That gave the tadpoles the ability to detect colors and follow optical patterns. The research was published in the Nature journal npj Regenerative Medicine.

Corresponding author Michael Levin, Ph.D., told FierceBiotechResearch in an interview that tadpoles provide the ideal model system for studying the brain’s ability to adjust to unnatural circumstances. “Through millions of years of evolution, the frog brain evolved to process visual data from two very specific spots in the head. We were interested to know how much plasticity is there,” said Levin, professor of biology and director of the Allen Discovery Center at Tufts and the Tufts Center for Regenerative and Developmental Biology. “If the brain finds itself in a radically altered body plan can it make adjustments?”

In this case, the tadpoles got a boost from Zomig, which works by activating two receptors known to play a role in neural development: serotonin receptors 1B and 1D (5-HT1B/D). After the treatment, 29% of tadpoles with eye grafts passed the color-detecting test, compared to 11% of tadpoles who got the eyes but not the drug. And 57% of treated tadpoles were able to follow optical patterns, vs. 32% of tadpoles that did not get the drug.

Levin and his team were surprised to discover that when they gave the tadpoles Zomig, the regeneration of neural connections was limited to the eyes. “So nerves that were sitting in the correct position, where they belonged, ignored [the treatment] completely, and only the nerves that found themselves in an aberrant site started to pay attention to these electrical cues,” Levin said. “This is really important, because it limits the side effects you might get from a treatment like this.”

The Tufts findings have implications not only for restoring sight, but for addressing a range of medical conditions, because it provides a basis for studying how cells determine whether they’re in the right or wrong position in the body, Levin said. Two potential applications are birth defects and cancer, he said. “In traumatic syndromes, you have anatomy that’s incorrect—cells that fail to do what they’re supposed to do,” Levin said. “Understanding and controlling how cells figure out where they are and whether they’re in the right or the wrong place is really going to be important for future applications.”

It could also have an impact on organ transplants, by improving the integration of implanted tissues with the nervous system. “There are all sorts of things that are being put into human bodies—bioengineered tissues, tracheas, bladders, hand and face transplants from donors,” Levin said. ”The goal is to make sure those structures are property innervated. It’s not just about eyes. It’s about almost anything you put into the body.”

Tufts’ Allen Discovery Center is supported by the Paul G. Allen Frontiers Group, launched last year by the Microsoft co-founder and philanthropist, and is comprised of biologists, engineers and computer scientists who are working together to unravel the mysteries of bioelectrical signaling in the body. The next step for the team working on the tadpole research is to study the promotion of innervation in mammals, Levin said. The researchers will also test methods for controlling where and how nerves are re-grown, in addition to examining brain plasticity in other senses, such as smell.

The tadpole experiment has one immediate takeaway that Levin hopes will provide inspiration to other scientists studying the brain and nervous system. “There are a lot of drugs out there for manipulating neurotransmitters that are already approved and being taken by people for anxiety, depression, epilepsy and other diseases,” he said. “They control the electric language that cells use to talk to each other and could form a powerful toolkit of reagents that can be repurposed for cancer, birth defects, regenerative medicine and more.”