Charlotte Ernstsen:
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Migraine is a primary headache disorder affecting more than 15% of the world’s population. It typically presents as a headache of moderate to severe intensity, often unilaterally, and lasting 4-72 hours. Despite years of research, the overall pathophysiology remains unclear. Different structures are known to be involved, such as the trigeminovascular system which includes the trigeminal ganglia, afferent neurons signaling to the meninges, and the meningeal arteries as well as higher brain structures and arteries in the head. Additionally, several signaling molecules and peptides play a role in migraine. These include nitric oxide (NO), calcitonin gene-related peptide (CGRP), and pituitary adenylate cyclase-activating peptide (PACAP-38).
Current treatments, such as triptans and CGRP/CGRP receptor monoclonal antibodies, primarily target the CGRP signaling pathway. While these treatments are beneficial for many patients, many side effects (triptans) and non-responding patients (CGRP antibodies) remain. For this PhD project, we sought to examine the migraine signaling cascade in three different studies to potentially help optimize current treatment strategies and/or find new treatment targets in migraine. We primarily used mouse models of provoked migraine in combination with genetic modifications (knockout mice) as well as molecular and ex vivo techniques. Migraine triggers that are known and validated in human migraine provocation studies were used for the mouse models. Such triggers include nitroglycerin (an NO donor), CGRP, and PACAP-38. In the mouse models von Frey filaments were used to measure tactile hypersensitivity which act as a surrogate marker for migraine-like pain as well as an indication of central activation of the nociceptive system. Migraine-specific drugs such as sumatriptan and CGRP receptor antagonist olcegepant were then used to block the induced hypersensitivity.
In the first study, we showed that combining two drugs with different mechanisms of action (sumatriptan and olcegepant) did not yield an additive effect in the nitroglycerin mouse model of provoked migraine. This is relevant to clinicians, now that gepants are being approved for marketing in Europe. Combining these new drugs with the classical, first-in-line migraine drug sumatriptan seems a straightforward clinical option. However, we argued that additional evidence was needed before implementing such a combination.
In the second study, we examined the interaction between central and peripheral CGRP signaling. Systemic administration of nitroglycerin induced cutaneous hypersensitivity in the mice which could be blocked by peripheral, but not intracerebroventricular, injections of both olcegepant and CGRP antibody. We argued that peripheral targeting of CGRP should be prioritized in the future.
Finally, in the third study, we examined the role of PACAP-38 in relation to CGRP. We found that PACAP-38 signals independently of both CGRP and its receptor. We also found that PACAP-38 could induce vasodilation of isolated arteries and is different from other migraine triggers such as nitroglycerin. We suggested that PACAP-38 could possibly be the dominating signaling molecule in patients not responding to CGRP-targeting treatments.
As described above, these studies serve as steps along the way to gain a better understanding of migraine. Hopefully, the studies conducted here will help advance migraine research, ultimately leading to optimized treatments for patients suffering from this debilitating disorder.