FINAL REPORT:  BiTox– a novel, non-paralytic, botulinum toxin A molecule for the treatment of chronic migraine (2016)

Summary

Chronic migraine is a disabling, underdiagnosed and undertreated disorder with a significant burden for society and the healthcare system. Botulinum toxin A (BoNT/A) is an established long-lasting preventive treatment for chronic migraine with a side effect profile that is often preferable by patients when compared to other preventive treatments. However, its toxicity and the muscle paralysis that occurs even with low doses, limit its efficacy. To overcome this, we developed a new BoNT/A-like molecule, BiTox, which lacks the known paralytic effects of native BoNT/A. We hypothesized that BiTox preserves its inhibitory actions on neurotransmitter release from sensory neurons, making it a pain-specific molecule that could be effective in reducing activation of the trigeminal pathway in animal models of migraine. We found that treatment with Bitox significantly increased the threshold of activation of trigeminal neurons to both mechanical and electrical stimulation. Additionally, BiTox significantly reduced the number of Fos-positive neurons in the trigeminocervical complex in the trigeminovascular migraine animal model.

 Hypothesis vs. Findings

Based on previous studies, we hypothesized that BiTox would reduce the CGRP levels released from trigeminal neurons. However, in this experimental setup, although both BoNT/A and Bitox reduced the concentration of CGRP released from treated cultures, the overall result was not significant. Nevertheless, a small number of CGRP expressing neurons were co-localized with cleaved SNAP25, the substrate of BoNT/A.

We also hypothesized that BiTox would be superior to BoNT/A in suppressing trigeminal activity. However, at a higher concertation than BoNT/A, BiTox inhibited trigeminal activity to a similar extent as BoNT/A. Regardless of this outcome, BiTox remains a strong novel anti-migraine agent that unlike BoNT/A, lacks any paralytic activity.

Unanswered Questions

Our studies showed that a recombinant BoNT/A molecule with reduced paralytic activity could be effective in suppressing trigeminovascular activity in animal models of migraine. A titration study identifying the optimum dose of BiTox that could produce a similar outcome remains to be done. Additionally, although we did not observe any side effects during the in vivo studies we performed with BiTox, we do not know if recombinant BoNT/A molecules might create an immune response different from the native BoNT/A.

What this Research Means to You

Our findings suggest that BiTox is a novel non-paralytic recombinant BoNT/A molecule with significant anti-migraine actions in the trigeminovascular system. This study introduces an untapped opportunity to develop a headache-specific treatment for chronic migraine.

FINAL REPORT: Investigating the Cortical Modulation of Trigeminocervical and Thalamic Function during Cortical Spreading Depression (2010)

This study won the 2010 Thomas E. Heftler Award.

Summary

About 15-20% of migraine patients have aura. The pathophysiology of aura is generally considered to be due to a wave of cortical spreading depression (CSD) spreading out from the occipital lobe across the cortex. Whether and through what mechanisms CSD and the resultant aura may be responsible for the initiation of head pain in migraine is still under discussion. Migraine pathophysiology is believed to involve activation, or the perception of activation, of primary trigeminal fibers innervating the meninges. These fibers project centrally on second order neurons within the trigeminocervical complex (TCC), before the signal is transmitted to the thalamus, and from there to the cortex where the pain matrix is processed. Both the TCC and the thalamus have been shown to have extensive fiber connections with the cortex. Thus, we hypothesize that a substantial cortical event such as CSD would be expected to influence the sensory responses of TCC and thalamic neurons.

In this study we investigated the potential effects of CSD in the transmission of nociceptive information within the TCC and sensory thalamus in animal models of migraine.

Hypothesis vs. Findings

Our experiments confirmed our initial hypothesis. The data demonstrate that CSD markedly alters neuronal firing of ipsilateral third order thalamic neurons and of contralateral trigeminocervical neurons, potentially though corticofugal projections in mice.

Unanswered Questions

The biggest challenge is to identify these mechanisms in migraine patients and how to best prevent them. Identifying the neurotransmitter pathways involved in these mechanisms may provide further insights on how to best treat migraine patients.

What This Research Means To You

The Migraine Research Foundation, through the Heftler Award, helped us demonstrate for the first time a new mechanism by which CSD may indeed induce central head pain via cortico-thalamic circuits and may shed more light on the relationship between aura and headache.

Learn More

In 2010, Anna P. Andreou, PhD was the winner of MRF’s Thomas E. Heftler Migraine Research Award. The award recognizes an outstanding young migraine researcher and supported Dr. Andreou’s project “Corticothalamic feedback and trigeminothalamic sensory processing during cortical spreading depression – relevance to migraine with aura.”

Dr. Andreou’s research took a novel look at how migraine with aura develops in the brain. She investigated potential activation of the thalamus gland during cortical spreading depression (CSD), a neurological phenomenon thought to be associated with migraine aura. She hoped to expand earlier research showing that the thalamus could become activated during CSD and pinpointing the exact pain pathways the thalamus affects. She hopes she and other migraine researchers will be busy for a long time exploring these new ideas and finding answers to migraine’s most difficult questions.

Dr. Andreou’s career has taken her around the world. She knew from a young age that she wanted to be a scientist, and decided on migraine research because of her interest in neurology and her own struggles with chronic migraine. Originally from Cyprus, she studied biology and neurophysiology as an undergraduate in Greece. She continued her studies at the Institute of Neurology at University College in London, where she earned her PhD. Dr. Andreou then worked as a post-doctoral fellow in the headache center at the University of California, San Francisco. She is now the Director of Headache Research at King’s College London.

Dr. Andreou enjoys being a scientist because her work gives her the opportunity to explore her own ideas and collaborate with others on their theories. She is very thankful to the Migraine Research Foundation for both supporting emerging researchers such as herself and raising money and awareness for migraine research. She notes that although migraine is the most common neurological disease and is very disabling, it is severely underfunded compared to other less-common conditions.