Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood-brain barrier permeability.
Cortical spreading depression (CSD) involves a slowly-propagating depolarization wave in the cortex, which can appear in numerous pathophysiological conditions, such as migraine with aura, stroke, and traumatic brain injury. Neurons and glial cells are also depolarized transiently during the phenomena. CSD is followed by a massive increase in glutamate release and by changes in the brain microcirculation. The aim of this study was to investigate the effects of two N-methyl-D-aspartate receptor antagonists, endogenous kynurenic acid (KYNA) and dizocilpine, on CSD and the related blood-brain barrier (BBB) permeability in rats. In intact animals, KYNA hardly crosses the BBB but has some positive features as compared with its precursor L-Kynurenine, which is frequently used in animal studies (KYNA cannot be metabolized to excitotoxic agents such as 3-hydroxy-L-kynurenine and quinolinic acid). We therefore investigated the possible effects of peripherally administered KYNA. Repetitive CSD waves were elicited by the application of 1 M KCl solution to the cortex. Direct current-electrocorticograms were measured for 1 hour. Four parameters of the waves were compared. Evans blue dye and fluorescent microscopy were used to study the possible changes in the permeability of the BBB. The results demonstrated that N-methyl-D-aspartate receptor antagonists can reduce the number of CSD waves and decrease the permeability of the BBB during CSD. These results suggest that KYNA itself or its derivatives may offer a new approach in the therapy of migraines.
Department of Physiology, Anatomy and Neuroscience, University of Szeged, Közép fasor 52, Szeged, Hungary.
Gáspár
G
Oláh
Judit
J
Herédi
Akos
A
Menyhárt
Zsolt
Z
Czinege
Dávid
D
Nagy
János
J
Fuzik
Kitti
K
Kocsis
Levente
L
Knapp
Erika
E
Krucsó
Levente
L
Gellért
Zsolt
Z
Kis
Tamás
T
Farkas
Ferenc
F
Fülöp
Arpád
A
Párdutz
János
J
Tajti
László
L
Vécsei
József
J
Toldi
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D013181:Cortical Spreading Depression / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008856:Microscopy, Fluorescence; D008881:Migraine Disorders / Q000188:drug therapy / Q000503:physiopathology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D018691:Excitatory Amino Acid Antagonists; D016291:Dizocilpine Maleate; D007736:Kynurenic Acid
NMDAR; blood–brain barrier; cortical spreading depression; glutamate receptors; kynurenic acid; kynurenines