FINAL REPORT: Preclinical Development of Nasal Insulin as a Therapy for Chronic Migraine (2010)

Published in Journal of Neurochemistry, Volume 122, Issue 1, July 2012

Summary

The overall goal of this grant was to develop nasal insulin as a preclinical therapy to reduce susceptibility to chronic migraine. We studied how insulin alters neural circuit electrical susceptibility to spreading depression, a most likely cause of episodic and, we hypothesize, chronic migraine.

The idea for this work stemmed from data showing that environmental enrichment (increased physical, social, and intellectual activity), which increases memory and learning, can reduce spreading depression in animals, and by extension, migraine in humans. Recently, nasal insulin has been used as an environmental enrichment and shown to be effective at reducing cognitive decline from Alzheimer’s disease. Accordingly, we reasoned that insulin might be similarly protective against spreading depression. We found that chronic insulin improved electrical function in hippocampal slice cultures grown over weeks, and used this pilot data to propose this grant. Our recent work involved extensive dose-response and time studies. We were able to show that insulin can acutely, and for days afterward, reduce susceptibility to spreading depression. This ‘proof of principle’ work has now been published, and is the first to show that an enrichment-based environment may provide novel therapeutics for migraine.

Hypothesis vs. Findings

Our hypothesis that insulin might be protective against spreading depression was validated by the current work.

Unanswered Questions

While we demonstrated the ‘proof of principle’ notion that insulin can reduce susceptibility to spreading depression, we need to extend this result to the in vivo condition. To-date our work with whole animals has been in designing and confirming the utility of a protocol for the effective nasal delivery of potential migraine therapeutics to the brain. With this accomplished, we next turned to improving models of whole animal spreading depression (involving both neocortex and hippocampus) that would allow us to detect subtle differences in therapeutic efficacy. This too has been accomplished, and we are now poised to study the use of insulin both in vivo and in vitro, using whole animals and hippocampal slice cultures. We expect this combination of models to provide detailed information about the potential clinical use and mechanisms of action of targeted therapeutics for chronic migraine.

What This Research Means to You

This Migraine Research Foundation grant helped us demonstrate for the first time that enrichment-based environments like insulin may be a novel source of effective therapeutics against high-frequency and chronic migraine.

FINAL REPORT: Microglia and Cytokines Modulate Chronic Migraine (2009)

Published in Dose-Response, Volume 8, Issue 4

Published in Journal of Neurochemistry, Volume 117, Issue 1

Summary

Chronic migraine is a prevalent healthcare burden whose cause is only partly known, a void that hampers development of new treatments. Considerable research shows that chronic pain, including that from migraine, may alter pain pathways so that they are more sensitive. This effect involves cytokines, small molecules first recognized for their role in signaling between immune cells. We hypothesized that pro-inflammatory cytokines produced after migraine could make it easier to trigger subsequent migraines as modeled by spreading depression, a most likely cause of migraine pain and aura.

We confirmed this hypothesis by triggering spreading depression in hippocampal slice cultures, thin sections of brain that can be kept in a dish for months. We found that spreading depression triggered cytokine changes in the brain that both increased and decreased susceptibility to spreading depression on subsequent days. Importantly, we also identified cytokine changes from neurons that prevented this increased susceptibility to spreading depression. Our work is the first to show that the interplay of cytokine changes between microglia and neurons may be ideal targets for the development of novel therapeutics to prevent migraine and its transformation to chronic migraine.

Hypothesis vs. Findings

We validated our hypothesis. First, we showed that spreading depression made it easier to elicit subsequent spreading depression days later. Second, we found this increased susceptibility was due to tumor necrosis factor alpha (TNF-α) signaling from microglia. Third, we extended our initial plans to include delineation of the cytokine signaling involved in cold-preconditioning neuroprotection.

This extension was based on our hypothesis that cold-preconditioning neuroprotection was also due to TNF-α from microglia. We confirmed this suspicion. Importantly, the gene screening involved with the work led to completely unexpected findings. We showed that interleukin-11 (IL-11), an anti-inflammatory cytokine, was produced by neurons and served to inhibit TNF-α signaling. Thus, when we blocked IL-11, cold-preconditioning was enhanced. This led us to speculate that IL-11 might prevent TNF-α-dependent increased susceptibility to spreading depression.  It did!

Finally, we entered into a collaborative effort with Marilyn Cipolla from the University of Vermont to examine how brain function is altered during pregnancy to resist seizure, and by extension, migraine, from peripheral pro-inflammatory changes. The rationale again is that pregnancy also raises TNF-α levels in the blood, as well as brain, yet susceptibility to seizures (and migraine) are reduced. Our work will define how the blood, blood brain barrier, and brain adapt to reduce brain excitability.

Unanswered Questions

We decided not to pursue the relation of TNF-α to reduced GABAergic function mediated by BDNF. The rationale for this move was based on work suggesting that paired pulse inhibition was too complex to be solely due to alterations in GABAergic function. We are now developing plans to resolve this impediment to experimental design.

Learn More

Ever since he was an undergraduate at Cornell College in Mt. Vernon, Iowa, Richard Kraig, MD, PhD, has had a profound interest in studying medicine. His professors encouraged the pursuit of new knowledge as a means to make a difference in the world. The education style at Cornell provided a progressive path to academic independence that included providing Dr. Kraig with his own laboratory where he was able to focus on an independent study project for more than two years. The freedom to pursue experiments led to his interest in neurology and the many mysteries of migraine. Dr. Kraig currently oversees the Cerebrovascular Disease and Aging Laboratories at The University of Chicago Medical Center, which focus on migraine, stroke, epilepsy and cognitive decline from aging. He also teaches undergraduate students, graduate students, medical students, and residents.

In 2009, the Migraine Research Foundation provided funding for Dr. Kraig’s ground-breaking study Microglia and Cytokines Modulate Chronic Migraine. This important project is the first to show the linkage between cytokine changes in microglia and neurons as ideal targets for the development of novel therapeutics to prevent migraine and its transformation to chronic migraine. Dr. Kraig has studied the phenomena of cortical spreading depression for over thirty-five years, and hopes that his research will reveal that it may be the underlying cause of migraine pain and aura.

In the next five years, Dr. Kraig and his team of researchers anticipate that their study will lead to clinical alternatives for migraine sufferers. His hope is that in the future, scientists will define the basic means by which physical, mental and social activities can lessen the impact of neurological disease and how understanding the mechanisms for this protection can lead to novel therapeutics for migraine.

In his spare time, Dr. Kraig enjoys working on his house, playing with his energetic dog and extending his G-gauge model railway. He also likes to dance the swing with his wife of forty years.