title: Kynurenines and PACAP in Migraine: Medicinal Chemistry and Pathogenetic Aspects.
abstract: BACKGROUND
  Migraine is a highly disabling neurovascular primary headache disorder, with its exact pathomechanism being still unrevealed. The current leading hypotheses are based on the sensitization and activation of the trigeminovascular system.
  
  
  OBJECTIVE
  To review the literature with focus on the effects of kynurenines (L-kynurenine and kynurenic acid) and pituitary adenylate cyclase-activating polypeptide on the regulation of the trigeminovascular system.
  
  
  METHODS
  A literature search was conducted to identify preclinical and clinical publications (198 references) by using the keywords 'kynurenines', 'pituitary adenylate cyclase-activating polypeptide', and 'migraine' in the database of MEDLINE/PubMed up to 10 September 2016 for topical review. Additional filters used included 'review', 'systematic review', 'original article', and 'English language'.
  
  
  RESULTS
  L-kynurenine and kynurenic acid act on the glutamatergic system at the level of the second-order nociceptive neurons in the trigeminal nucleus caudalis. Pituitary adenylate cyclase- activating polypeptide is released from the peripheral nerve endings of the trigeminal pseudounipolar neurons and causes vasodilation and mast cell degranulation, leading to consequent peripheral sensitization of the dural nociceptors. Centrally released pituitary adenylate cyclase-activating polypeptide in the trigeminal nucleus caudalis results in the central sensitization of the second-order neurons. The sensitization process leads to the characteristic features of migraine.
  
  
  CONCLUSIONS
  L-kynurenine, kynurenic acid, and pituitary adenylate cyclase-activating polypeptide may have fundamental roles in the initiation of migraine headache attacks.
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6., H-6725, Szeged, Hungary.
authors.forename: Janos
authors.initials: J
authors.lastname: Tajti
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6., H-6725, Szeged, Hungary.
authors.forename: Delia
authors.initials: D
authors.lastname: Szok
authors.affiliation: MTA-SZTE Neuroscience Research Group, Semmelweis u. 6., H-6725, Szeged, Hungary.|Faculty of Health Sciences and Social Studies, University of Szeged, Temesvari krt. 31., H-6726, Szeged, Hungary.
authors.forename: Gabor
authors.initials: G
authors.lastname: Nagy-Grocz
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6., H-6725, Szeged, Hungary.|MTA-SZTE Neuroscience Research Group, Semmelweis u. 6., H-6725, Szeged, Hungary.
authors.forename: Bernadett
authors.initials: B
authors.lastname: Tuka
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6., H-6725, Szeged, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Petrovics-Balog
authors.affiliation: Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép fasor 52., H-6726, Szeged, Hungary.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Toldi
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6., H-6725, Szeged, Hungary.|MTA-SZTE Neuroscience Research Group, Semmelweis u. 6., H-6725, Szeged, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Vecsei
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007737:Kynurenine / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D008881:Migraine Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000737:chemistry / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016194:Receptors, N-Methyl-D-Aspartate; D007737:Kynurenine; D018698:Glutamic Acid
keywords: Glutamate; kynurenine; migraine; mode of action; pathomechanism; pituitary adenylate cyclaseactivating
  polypeptide