Song Guo

Song Guo, MD, PhD

Pain mechanisms of migraine for identification of new drug targets

Migraine is a widespread and debilitating neurological disorder with high socioeconomic costs. For this reason more effective migraine therapies are highly needed. Over the last 30 years our group has developed migraine provocation studies contributing to identification of at least two endogenous neuropeptides that induce migraine attacks in patients: calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclaseactivating peptide-38 (PACAP38). Recently, development and introduction of monoclonal antibodies (mAbs) blocking the CGRP signaling pathway is the first mechanism-based treatment showing efficacy and thus the most important advance in migraine therapy in decades. However, 40% of patients are unresponsive to drugs
inhibiting the effects of CGRP. We believe that PACAP38 may be a critical player in these patients.

Supporting this hypothesis is our unpublished data showing that PACAP38 can generate migraine-like pain in mice without a functioning CGRP pathway. Furthermore, we have shown that PACAP38 is involved in migraine pathogenesis through the trigeminovascular system and causes perivascular inflammation. The objective of our present project is therefore to dissect how PACAP38 results in pro-nociceptive actions in our rodent models of migraine. We will, for the first time, focus on its known receptors (PAC1, VPAC1, VPAC2 and MrgB3) using knock-out mice for its receptors and combine these with investigations of mast cell degranulation. In addition, we will conduct a study with PACAP38-inhibiting mAbs developed by Lundbeck to understand how blocking of PACAP38 itself correlates with inhibition of its receptors. Understanding the site and mechanisms of action may identify more specific drug targets and predict or improve efficacy of PACAP38-inhibiting therapies and further revolutionize the management of migraine.

Mentors:

Basic mentor: Anders Hay-Schmidt, Professor, Department of Odontology, Panum Institute, The Faculty of Health, University of Copenhagen

Clinical mentor: Messoud Ashina, Clinical Professor in Neurology, Director of Human Migraine Research Unit, The Danish Headache Center & Department of Neurology, Rigshospitalet-Glostrup
Supplementary clinical mentor: Jes Olesen, Clinical Professor in Neurology, Leader of Migraine Basic Research Group at Glostrup Research Institute, The Danish Headache Center, Rigshospitalet-Glostrup
Life science industry mentor: Ayodeji Asuni, Discovery Project Leader/Principal Scientist, Department of Neuroscience, H. Lundbeck A/S