CSD, BBB and MMP-9 elevations: animal experiments versus clinical phenomena in migraine

Abstract

Cortical spreading depression (CSD) has been at the center stage of migraine pathophysiology for approximately six decades. Reanalysis of CSD reveals several major unbridgeable gaps in this experimental neurophysiologic concept for migraine. Key phenotypic and pharmacological features of migraine challenge the assumed pathophysiologic role of CSD. Detection of subclinical infarct-like white matter lesions (WMLs) in the brain of some migraine patients stimulated the concept of CSD-related BBB disruption. Raised plasma levels of matrix metalloproteinases (MMPs) in migraine patients in the headache phase, specifically MMP-9, suggested a pathogenetic role for MMP elevation in the development of both migraine attacks and WMLs. Migraine attacks with or without aura present a unique, profound and protracted vasodilatory challenge to the homeostatic systems of the brain. To accommodate the rather sudden increase in cerebral blood flow, the brain circulatory network must dilate and the BBB must expand considerably. MMPs can influence expansion of the extracellular matrix of the BBB and loosening of the intercellular tight junctions between endothelial cells through proteolytic degradation during migrainous cerebrovascular dilatation. WMLs most probably reflect transient and discrete breakdown of the BBB consequent to sustained cerebral hyperperfusion rather than hypoperfusion. Systemic elevations of MMPs are not specific to migraine but are found in a variety of neurological and extra-neurological disorders. This perspective presents a conceptual dissociation between the effects of CSD on the brain of experimental animals and the clinical phenomena in migraine patients.

Keywords::

• BBB
• botulinum toxin
• cortical spreading depression
• extracellular matrix
• matrix metalloproteinase
• migraine
• patent foramen ovale
• white matter lesion

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Notes

CSD: Cortical spreading depression.