http://www.ncbi.nlm.nih.gov/pubmed/27130315
J Headache Pain. 2015 Dec;17(1):47. doi: 10.1186/s10194-016-0638-5. Epub 2016 Apr 29.
Altered kynurenine pathway metabolites in serum of chronic migraine patients.
Curto M1,2,
Lionetto L3,
Negro A4,5,
Capi M3,
Fazio F6,
Giamberardino MA7,
Simmaco M3,
Nicoletti F6,8,
Martelletti P4,5.
Abstract
BACKGROUND:
Activation
of glutamate (Glu) receptors plays a key role in the pathophysiology of
migraine. Both NMDA and metabotropic Glu receptors are activated or
inhibited by metabolites of the kynurenine pathway, such as kynureninic
acid (KYNA), quinolinic acid (QUINA), and xanthurenic acid
(XA). In spite of the extensive research carried out on KYNA and other
kynurenine metabolites in experimental models of migraine, no studies
have ever been carried out in humans. Here, we measured all metabolites
of the kynurenine pathway in the serum of patients affected by chronic
migraine (CM) and age- and gender-matched healthy controls.
METHODS:
We
assessed serum levels of tryptophan (Trp), L-kynurenine (KYN), KYNA,
anthranilic acid (ANA), 3-hydroxyanthranilic acid (3-HANA),
3-hydroxykynirenine (3-HK), XA, QUINA, and 5-hydroxyindolacetic acid
(5-HIAA) in 119 patients affected by CM (ICHD-3beta criteria) and 84
age-matched healthy subjects. Patients with psychiatric co-morbidities,
systemic inflammatory, endocrine or neurological disorders, and mental
retardation were excluded. Serum levels of all metabolites were assayed
using liquid chromatography/tandem mass spectrometry (LC-MS/MS).
RESULTS:
LC-MS/MS
analysis of kynurenine metabolites showed significant reductions in the
levels of KYN (-32 %), KYNA (-25 %), 3-HK (-49 %), 3-HANA (-63 %),
5-HIAA (-36 %) and QUINA (-80 %) in the serum of the CM patients, as
compared to healthy controls. Conversely, levels of Trp, ANA and XA were
significantly increased in CM patients (+5 %, +339 % and +28 %,
respectively).
CONCLUSIONS:
These
findings suggest that in migraine KYN is unidirectionally metabolized
into ANA (anthranilte) at expenses of KYNA and 3-HK. The reduction in the levels of
KYNA, which behaves as a competitive antagonist of the glycine site of
NMDA receptors, is consistent with the hypothesis that NMDA receptors
are overactive in migraine. The increase in XA, a putative activator of
Glu2 receptors, may represent a compensatory event aimed at reinforcing
endogenous analgesic mechanisms. The large increase in the levels of ANA
encourages research aimed at establishing whether ANA has any role in
the regulation of nociceptive transmission.
KEYWORDS:
Chronic migraine; Glutamate; Kynurenine; Metabotropic Glu receptors; NMDA receptors; Pain
Inga kommentarer:
Skicka en kommentar