DOI

10.17077/etd.6fnasdq1

Document Type

Dissertation

Date of Degree

Fall 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Neuroscience

First Advisor

Andrew Russo

First Committee Member

Michael Dailey

Second Committee Member

George Richerson

Third Committee Member

Kumar Narayanan

Fourth Committee Member

Daniel Tranel

Abstract

Migraine affects ~15% of the US population (nearly 40 million people), making it one of the most common neurological disorders; however currently available therapeutic options for migraine relief are often ineffective. Moreover, acute and prophylactic drugs are both commonly associated with contraindications and serious side effects, and routine use of acute treatments may result in medication overuse-headaches.

Elevated levels of the neuropeptide calcitonin gene-related peptide (CGRP) are known to be a primary factor in migraine pathogenesis, although the mechanisms by which CGRP expression becomes errantly modulated are unclear. CGRP is a product of the trigeminal ganglion and can be released both peripherally onto the dura mater, leading to neurogenic inflammation, and centrally at the spinal trigeminal nucleus, leading to neuromodulation. A great deal of CGRP-relevant migraine research has focused on the trigeminovascular system, but whether the cerebral cortex may have a role in migraine pathophysiology been less well studied.

A subset of migraineurs experience a premonitory aura, which often manifests as a disturbance in one visual hemifield. An aberration called cortical spreading depression (CSD) is the likely electrophysiological substrate of the migraine aura, but whether CSD and CGRP are functionally related is not known. CSD is characterized by an initial transient wave of neuronal and glial depolarization, followed by a prolonged period of quiescence that is largely refractory to subsequent stimulation.

Converging evidence supports a facilitatory role for cortical spreading depression (CSD) in migraine with and without aura, and CSD propagation has been shown to be dependent on functional CGRP receptors. Moreover, reported effects of CSD overlap with those of CGRP-mediated neurogenic inflammation.

The experiments described herein seek to test the hypothesis that induction of CSD in vivo will lead to increased CGRP expression in the rodent cerebral cortex. Preliminary data in rats suggests that 3M KCl-induced CSD can trigger increased CGRP expression in the ipsilateral cortex. Preliminary data in mice has been less conclusive. Presented here are the data obtained from mice and rats, as well as speculation on the cause(s) of the differences in CGRP expression between species and how these findings relate to human studies.

Public Abstract

Migraine affects an estimated 40 million Americans (nearly 15% of the population), making it one of the most common neurological disorders in the United States. An estimated 113 million days of work are lost yearly due to migraine, with the total financial toll of migraine in the US approaching $100 billion annually. Furthermore, migraine affects predominantly women in their reproductive years, which poses unique hardships for young mothers and their families.

Migraine sufferers frequently report dissatisfaction with currently available treatment options, and up to half of migraine sufferers report that they are unable to manage their symptoms with currently available therapeutics. A major reason for the lack of effective treatments is an incomplete understanding of what occurs in the body to predispose someone to developing migraine.

Calcitonin gene-related peptide (CGRP) is a small protein that is widely present in the human body. For unknown reasons, migraine sufferers are particularly sensitive to CGRP; indeed, intravenous administration of CGRP to a migraine patient is likely to elicit a migraine, whereas a similar dose of CGRP to a non-migraineur would be rather innocuous. Moreover, drugs that block the effects of CGRP can prevent migraine development.

Despite the identification of CGRP as having a pivotal role in migraine, neither the events that spur elevated CGRP expression nor its subsequent effects are known. This thesis presents data suggesting that an abnormal brain event, cortical spreading depression (CSD), could play a role in abnormal regulation of CGRP in the cerebral cortex.

Keywords

cgrp, cortical spreading depression, migraine

Pages

xv, 107 pages

Bibliography

Includes bibliographical references (pages 97-107).

Copyright

Copyright © 2016 Anne Elizabeth Tye

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