Kynurenine metabolites and migraine: experimental studies and therapeutic perspectives

Abstract

Migraine is one of the commonest neurological disorders. Despite intensive research, its exact pathomechanism is still not fully understood and effective therapy is not always available. One of the key molecules involved in migraine is glutamate, whose receptors are found on the first-, second- and third-order trigeminal neurones and are also present in the migraine generators, including the dorsal raphe nucleus, nucleus raphe magnus, locus coeruleus and periaqueductal grey matter. Glutamate receptors are important in cortical spreading depression, which may be the electrophysiological correlate of migraine aura. The kynurenine metabolites, endogenous tryptophan metabolites, include kynurenic acid (KYNA), which exerts a blocking effect on ionotropic glutamate and α7-nicotinic acetylcholine receptors. Thus, KYNA and its derivatives may act as modulators at various levels of the pathomechanism of migraine. They can give rise to antinociceptive effects at the periphery, in the trigeminal nucleus caudalis, and may also act on migraine generators and cortical spreading depression. The experimental data suggest that KYNA or its derivatives might offer a novel approach to migraine therapy.

Keywords: Cortical spreading depression; glutamate; kynurenic acid; kynurenine metabolites; migraine; migraine generators; trigeminal system..

Fig. (1)

The kynurenine pathway.

Fig. (2)

Effects of kynurenine metabolites on the structures of nervous system, which are important in the pathomechanism of migraine and pain. 3-HA: 3-hydroxyanthranilic acid, 5,7-DCK: 5,7-dichlorokynurenic acid, 7-CK: 7-chlorokynurenic acid, ANA: anthranilic acid, CSD: cortical spreading depression, DRG: dorsal root ganglion, DRN: dorsal raphe nucleus, KYNA: kynurenic acid, LC: locus coeruleus, L-KYN: L-kynurenine, NRM: nucleus raphe magnus, PAG: periaqueductal grey matter, QUIN: quinolinic acid, TG: trigeminal ganglion, TNC: trigeminal nucleus caudalis, TRP: tryptophan, XA: xanthurenic acid; ↑: increased concentration.

Fig. (3)

Effects of kynurenine metabolites on the nervous structures involved in the pathogenesis of migraine. 7-CK: 7-chlorokynurenic acid, CSD: cortical spreading depression, DRN: dorsal raphe nucleus, IV: fourth ventricle, KYNA: kynurenic acid, LC: locus coeruleus, L-KYN: L-kynurenine, NRM: nucleus raphe magnus, PAG: periaqueductal grey matter, QUIN: quinolinic acid, TG: trigeminal ganglion, TNC: trigeminal nucleus caudalis; ↑: increased concentration.