title: Migraine aura: new information on underlying mechanisms.
abstract: OBJECTIVE
  Since the initial description of cortical spreading depression by Leao, evidence that cortical spreading depression is the underlying pathomechanism of migraine aura has increased. The purpose of this review is to describe the ultimate genetic and molecular mechanisms of migraine aura.
  
  
  RESULTS
  It has been debated how a primarily cortical phenomenon (aura phase) may activate trigeminal fibres (headache phase). Recent data have demonstrated a link between cortical events and activation of the pain-sensitive structures of the dura mater. The initial cortical hyperperfusion in cortical spreading depression is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibres, whereas delayed meningeal blood flow increase is mediated by a trigeminal-parasympathetic brainstem connection. With regard to molecular mechanisms, cortical spreading depression upregulates a variety of genes coding for COX-2, TNF-alpha and IL-1beta, galanin or metalloproteinases. The activation of metalloproteinases leads to leakage of the blood-brain barrier, allowing potassium, nitric oxide, adenosine and other products released by cortical spreading depression to reach and sensitize the dural perivascular trigeminal afferents. In familial hemiplegic migraine, new mutations have been described in chromosome 1q23, leading to a haploinsufficiency of the sodium/potassium pump, producing an increase in intracellular calcium, similar to the CACNA1A mutation.
  
  
  CONCLUSIONS
  Recent studies have helped unravel the basic mechanisms involved in migraine aura. Far from being a simple phenomenon, a sequence of events leads from the cortex to the activation of pain-sensitive structures. The role of the brainstem is still poorly described. The identification of target molecules may provide new therapies.
authors.affiliation: Headache Program, Department of Neurology, Hospital Ruber Internacional, Madrid, Spain and Department of Neurology, Charité, Universitätsmedizin Berlin, Berlin, Germany. msanchezdelrio@ruberinternacional.es
authors.forename: Margarita
authors.initials: M
authors.lastname: Sánchez-del-Rio
authors.forename: Uwe
authors.initials: U
authors.lastname: Reuter
mesh_terms: D000818:Animals; D013181:Cortical Spreading Depression; D005786:Gene Expression Regulation; D006801:Humans; D020325:Migraine with Aura / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D009569:Nitric Oxide / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D009569:Nitric Oxide