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Nasal Spray Reduces Migraine-Related Stress, Peptides

Richard Kraig

Richard Kraig (University of Chicago)

10 Feb. 2020. A hormone resembling insulin given as a nasal spray is shown in lab rats to reduce stress on nerve cells and peptides associated with migraine pain. Researchers from University of Chicago and a spin-off company licensing the technology, describe their findings in the April 2020 issue of the journal Brain Research.

UChicago neuroscientist Richard Kraig and researcher Lisa Won study chemical changes in the brain associated with spreading depression, a condition that results in abrupt changes in electrical activity of nerve cells, also found in people with migraine and other neurological disorders. Migraine is a neurological syndrome causing severe headaches along with nausea, vomiting, and extreme sensitivity to light and sound. The web site estimates 37 million people in the U.S. suffer from migraines, and cites World Health Organization data indicating migraines affect 18 percent of American women and 7 percent of men.

Previous work in Kraig’s lab identified a mechanism in the brain, where spreading depression is brought on by oxidative stress that results from imbalances in oxygen atoms affecting mitochondria, the energy centers of cells. Spreading depression and its associated oxidative stress also create hyperexcitability that in turn produce more oxidative stress, creating a feedback loop that exacerbates migraine pain.

Kraig and Won also found other chemical changes associated with oxidative stress and migraine. The calcitonin gene-related peptide, or CGRP, is released by sensory nerves and linked to pain responses, with compounds that limit or block CGRP gaining more interest as candidates for treating migraine. The researchers discovered as well that the trigeminal ganglion, a collection of 12 cranial nerves that provides facial sensations, reacts to oxidative stress by releasing more CGRP, and lowering the threshold for spreading depression.

The Chicago team tested a treatment candidate for reducing oxidative stress, a hormone known as insulin-like growth factor-1. This hormone is a peptide chemically similar to insulin produced by the pancreas for regulating blood sugar, and approved by FDA as a growth hormone for children. Kraig and Won are seeking a treatment that reduces the oxidative stress triggering the cascade of chemical reactions associated with migraine, and believe insulin-like growth factor-1 may help reduce the incidence of migraines in people with frequent episodes.

The researchers formulated insulin-like growth factor-1 as a nasal spray, to provide a more direct path to the brain than most oral drugs. Kraig and Won tested insulin-like growth factor-1, delivered as a nasal spray, with lab rats. The rats, in this case, were chemically induced to experience spreading depression, and given either the hormone or a placebo compound as a nasal spray.

Nerve fibers taken from the trigeminal ganglion in euthanized rats receiving the hormone or placebo show the animals have an 81 percent lower level of CGRP one day after the hormone nasal spray, while placebo recipients show no difference. The team also checked the rats for signs of the insulin-resembling hormone on blood glucose levels, and found no changes in blood glucose among the animals.

In 2016, Kraig with scientist-entrepreneurs Martin Sanders and Yuan Zhang founded Seurat Therapeutics to take the lab’s research on insulin-like growth factor-1, or IGF-1, and oxidative stress to market. The Chicago company licenses the Kraig lab’s technology and is incubating in the university’s entrepreneurship center. According to Crunchbase, Seurat Therapeutics so far raised $1.3 million in seed funding.

The company is continuing its preclinical studies and optimistic about prospects for its migraine treatment. “The fact that IGF-1 is a molecule that is FDA-approved for treatment of growth hormone factor deficiency in children for over 20 years,” says Sanders in a university statement, “can de-risk parts of Seurat’s future research and development process, since historical data suggests the drug could be well-tolerated.”

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