Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood–brain barrier permeability

Abstract

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.

Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders

“…In addition to PIP, BBB paracellular permeability has been observed to increase during familial hemiplegic migraine and in animal models of migraine ( Gursoy-Ozdemir et al, 2004 ; Dreier et al, 2005 ; Olah et al, 2013 ). In a model of cortical spreading depression (CSD), Evans blue and plasma protein extravasation was associated with an increase in MMP-9 expression and activity and a decrease in ZO-1 expression in brain microvessels ( Gursoy-Ozdemir et al, 2004 ).…”

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

“…Quite apart from the neuroimmunological activity of quinolinic acid, it can increase the permeability of the bloodbrain barrier (149)(150)(151)(152), an effect intriguingly opposed by kynurenic acid (153). Not only would this allow inflammatory mediators easier access to the CNS cells but it would also facilitate passage of leukocytes directly into the brain parenchyma.…”

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

“…Therefore, the neuroprotective property of KYNA could be due to its antagonistic activity toward the NMDA receptor [15], and/or anti-inflammatory and antioxidant effects [39,40]. Previous studies have shown that KYNA crosses the blood brain barrier poorly [29,30]. It was therefore reasonable to assume similar poor crossing through the blood retinal barrier.…”

“…To determine whether the KYNA is neuroprotective in the retina, we first investigated whether it is permeable to the blood retinal barrier, although KYNA has been reported to be poorly permeable to the blood brain barrier [29,30]. We injected KYNA intravenously into WT mice and measured its levels in the serum and retina after 2 h. We found a significant increase in KYNA levels both in serum and retinas of KYNA injected mice compared to sodium phosphate buffer-injected control mice (Supplementary Figure S1).…”