Date of Degree
PhD (Doctor of Philosophy)
Molecular Physiology and Biophysics
Andrew F. Russo
Migraine is a debilitating neurological disorder, which affects over 10% of the general population. In addition to headache, migraine includes a host of associated symptoms, such as nausea and hypersensitivity to light, noise, and touch. While great strides have been made in migraine treatment in recent decades, the basic biological and pathophysiological mechanisms underlying migraine are still not well understood. Pain signals travel via a polysynaptic pathway from the periphery to the cortex, where conscious perception of pain occurs. This multi-neuron pathway produces a message that can be modified at any step of its transit.
One peptide that may modify this pathway is calcitonin gene-related peptide (CGRP). CGRP is a potent vasodilator and neuromodulator, and mounting evidence suggests CGRP may play a causative role in migraine. CGRP levels are increased during migraine, but can be reduced upon successful treatment with drugs in the triptan class. Importantly, injection of CGRP into migraine patients can elicit a delayed, migraine-like headache. Finally, CGRP receptor antagonists are clinically effective in providing relief to migraine patients. In addition to CGRP, the CGRP gene (CALCA) expresses another peptide that may also be relevant to migraine. Procalcitonin (proCT) is a recognized biomarker for sepsis, but emerging evidence suggests it may have actions similar to CGRP in migraine. First, proCT has biological activity at the CGRP receptor. Second, proCT is reported to be increased during migraine.
We hypothesized that regulation of CGRP and proCT may be altered in migraineurs, and that migraineurs may also be sensitized to the effects of these peptides. To study the role of these peptides in migraine pathways, a number of methods have been employed. Studies exploring regulation of gene expression were performed in cultured trigeminal ganglia, as well as primary cultures of trigeminal and cortical glia. These studies show that the Calca gene can be regulated by a number of stimuli, including hypoxia and reactive oxygen species. These insults have the ability to induce CALCA gene and peptide expression to varying degrees on different cell types. In addition to in vitro experiments on Calca gene regulation, the in vivo effects of CGRP on mouse behavior were also investigated. Animals were genetically sensitized to CGRP via overexpression of the rate-limiting CGRP receptor subunit. In these animals, injection of CGRP is sufficient to induce light aversion, which is used to model photophobia. Physiological and biochemical triggers of migraine were tested using this behavioral paradigm. While stress and mast cell degranulation are sufficient to induce light aversion, the role of CGRP in these events remains unclear, as both CGRP sensitized and control animals displayed a light aversion phenotype. Together, these studies show the dynamic regulation of the Calca gene in migraine pathways as well as highlight some of the challenges of modeling a complex disease in an animal model.
calcitonin gene-related peptide, cortical spreading depression, migraine
xiii, 147 pages
Includes bibliographical references (pages 120-147).
Copyright 2013 Ann Christine Raddant