Roughly 30 million Americans suffer from migraines, and as you might expect, there’s a large pharmaceutical market to prevent or stop these debilitating headaches. Drugs such as Imitrex and Verapamil employ different pharmacological modes of action, reducing migraines by adjusting neurotransmitter levels, blocking ion channels, or simulating the body’s natural painkillers. There’s also a less pharmaceutical migraine treatment strategy, recommended by many headache specialists, that follows the old adage: “Active Body, Active Mind.” One recent study even found that 40 minutes of exercise three times a week can be as effective at preventing migraines as popular anti-migraine medications.
Still, prescribing exercise or environmental enrichment (keeping the mind busy through activities such as reading, crossword puzzles, exercise, or socialization) can strike some doctors and patients as frustratingly vague. Understanding the biological mechanism that makes these activities protective against migraines could help convince doctors and patients of their utility, while also giving researchers the opportunity to translate the factors associated with environmental enrichment into highly effective treatments. In the laboratory of Richard Kraig, William D. Mabie Professor in the Neurosciences at University of Chicago Medicine, that very effort is underway.
“We are interested in environmental enrichment as a way to stop cognitive decline from aging, injury after stroke, Parkinson’s disease, and cell death after seizures. With our new work, we apply this search for how the brain protects itself against disease to include migraines,” Kraig said. “The ‘why’ of it has sometimes been left in the realm of holistic medicine, with little scientific support. So establishing the hard science makes it more credible to the psychologists, physiologists, physiatrists, because here’s the chemistry.”
Working with graduate students Yelena Grinberg and Aya Pusic as well as senior technician Heidi Mitchell, Kraig discovered three different natural signals elevated by exercise and environmental enrichment: insulin-like growth factor-1 (IGF-1), interleukin-11 (IL-11), and interferon gamma (IFN-γ). When these “cytokines” are applied to brain slices, they reduce the probability of triggering a spreading depression — a transient wave of reduced brain activity associated with migraines. Understanding how those cytokines stop spreading depression — and the nasal route by which they might be delivered — may revolutionize how migraines and other neurological conditions are treated.
A spreading depression of brain is a chain reaction of dramatic events. After an initial burst of increased neuronal activity, a subsequent ripple of absent activity slowly spreads across involved brain at a rate of about 3 mm per minute — lasting a few minutes overall. While the event sounds brief, the consequences can last from hours to days, causing harmful oxidative stress, elevated inflammatory factors, moving microglia, and significant pain and discomfort for the migraine sufferer.
Paradoxically, the way to stop this chain reaction may not be to simply reduce or block the byproducts of a spreading depression, but to expose the brain to moderate levels of inflammatory factors, which include the cytokines described above. To interrupt the cycle of repeated migraines, treatments could take place before the process begins or in small steps after the recurrent spreading depression that underlies chronic migraine. While these factors may have negative effects in the short-term, in the long-term they prime the neurons to make antioxidants that are protective against oxidative stress.
“Spreading depression increases oxidative stress in a big fashion — it depolarizes all the brain cells. It’s like an engine kicking out a lot of exhaust, and the exhaust makes the brain hyper-excitable,” Kraig said. “But you have to let the engine run. The engine is running with stimuli that include cytokines that are initially irritative, but then adapt to stop spreading depression.”
The trick, Kraig said, is to mimic the natural cycles of cytokine levels the brain would experience during healthy, active behavior, rather than drowning the system in abnormally high concentrations of the factors that can occur with disease. The cytokines would be delivered to the brain in an on/off pattern rather than chronically, theoretically recreating the rise and fall of natural cytokines during a person’s sleep/wake cycle. By giving just a little bit of a factor normally considered harmful, the treatment could strengthen the brain’s resistance to spreading depression and migraines via the principle of hormesis, or “what doesn’t kill me makes me stronger.”
“The treatment is unique in that it’s the opposite of putting a Band-Aid on something,” Grinberg said. “It’s triggering cells to produce their own antioxidants instead of just providing the antioxidants exogenously. In that way it’s really unique and the opposite of how a lot of people think about medical treatment.”
Another logistical question remains: how do you get those cytokines to the brain? The body protects its most important organ with the blood-brain barrier, a biological wall that prevents most drugs given orally or intravenously from entering the brain. To solve this problem, Kraig’s laboratory has proposed borrowing a drug delivery system best known for allergy sufferers: nasal spray. For migraine, nasal delivery could be focused directly to the brain. In theory, a spritz up the nose of IGF-1, IL-11, IFN-γ, or some combination of the three once a day might provide the necessary protection to ward off migraines.
“It’s a selective brain delivery and it’s really efficient. It’s impressive how well it works,” Grinberg said.
The laboratory has filed patents for their new treatment idea, but much more science remains to be done. While the brain slice experiments have confirmed a protective effect of cytokines against spreading depression, the same effect must be proved in whole animals before the concept can be considered for testing in humans. The laboratory is also testing whether a combination of the cytokines will be more effective than any individual factor, as well as other pressing questions of how best to use this potential new weapon against migraines.
“I think it has an extremely valuable conceptual advantage for patients, because it is derived from naturally occurring signaling by which the immune and nervous systems interact to improve brain health,” Kraig said. “Our hope is not only to develop novel therapeutics for migraine but to empower patients with the knowledge of how enrichment can lessen the severity of their migraines.”
[Photo of nasal spray by robin_24, from Wikimedia Commons.]