Spreading depression: from serendipity to targeted therapy in migraine prophylaxis

CURRENT REVIEW: CLINICAL SCIENCE

Spreading depression: from serendipity to targeted therapy in migraine prophylaxis

C Ayata

Stroke and Neurovascular Regulation Laboratory, Department of Radiology, and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Correspondence to Cenk Ayata, 149 13th Street, Room 6408, Charlestown, MA 02129, USA. e-mail: cayata@partners.org
Cephalalgia. Volume 29 Issue 10, Pages 1095 - 1114

Published Online: 7 Sep 2009

Copyright © 2009 International Headache Society

ABSTRACT

Despite the relatively well-characterized headache mechanisms in migraine, upstream events triggering individual attacks are poorly understood. This lack of mechanistic insight has hampered a rational approach to prophylactic drug discovery. Unlike targeted abortive and analgesic interventions, mainstream migraine prophylaxis has been largely based on serendipitous observations (e.g. propranolol) and presumed class effects (e.g. anticonvulsants). Recent studies suggest that spreading depression is the final common pathophysiological target for several established or investigational migraine prophylactic drugs. Building on these observations, spreading depression can now be explored for its predictive utility as a preclinical drug screening paradigm in migraine prophylaxis.

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DIGITAL OBJECT IDENTIFIER (DOI)

10.1111/j.1468-2982.2009.01982.x

Cortical spreading depression—new insights and persistent questions

CURRENT REVIEW: BASIC SCIENCE

Cortical spreading depression—new insights and persistent questions

A Charles & KC Brennan

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Correspondence to Andrew Charles, 635 Charles Young Drive Suite 575, Los Angeles, CA 90095, USA. Tel. +1-310-794-1870, fax +1-310-206-6906, e-mail acharles@ucla.edu
Cephalalgia Volume 29 Issue 10, Pages 1115-1124

Published Online: 7 Sep 2009

Copyright © 2009 International Headache Society

ABSTRACT

Since its original extensive description by Leao in 1944, thousands of publications have characterized the phenomenon of cortical spreading depression (CSD). Despite the attention that CSD has received over more than six decades, however, many fundamental questions regarding its initiation, propagation, functional consequences, and relationship to migraine and other human disorders remain unanswered. Advances in genetics and cellular imaging have led to important insights into the basic mechanisms of CSD, with increasing attention focused on specific neuronal ion channels, neurotransmitters and neuromodulators. In addition, there is growing recognition that astrocytes and the vasculature may play an active, rather than simply a passive or reactive role in CSD. Several recent descriptions of CSD in humans in the setting of brain injury provide definitive evidence that this phenomenon can occur and have important functional consequences in the human brain. Although the exact role of CSD in migraine has yet to be conclusively established, there is strong evidence that the investigation of CSD in animal models can provide meaningful information about migraine that can be translated into the clinical setting. This review will briefly address the extensive work that has been done on CSD over more than half a century, but focus primarily on more recent studies with a particular emphasis on relevance to migraine.

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DIGITAL OBJECT IDENTIFIER (DOI)

10.1111/j.1468-2982.2009.01983.x