Kynurenines and headache.

In parallel to serotonin synthesis, the major route of tryptophan catabolism is the kynurenine pathway, which produces neuroactive metabolites. Among these substances, kynurenic acid has potential neuroprotective action blocking glutamate release and glutamatergic neurotransmission. Glutamate is a key player in migraine pathogenesis; it is crucial in the communication of first and second-order neurons, and it has an important role in the genesis of cortical spreading depression, which is the electrophysiological correlate for migraine aura and may be involved in the activation of the trigeminal system. Thus, kynurenines may affect the pathogenesis directly, by acting on glutamate receptors and exerting other neuromodulatory effects, and indirectly via an altered serotonin metabolism. This work summarizes our current results regarding the role of the kynurenine system in trigeminal activation and other events occurring during migraine headache.

Kynurenine metabolites and migraine: experimental studies and therapeutic perspectives.

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.

Kynurenate derivative attenuates the nitroglycerin-induced CamKIIα and CGRP expression changes.

OBJECTIVE: To examine the efficacy of L-kynurenine and a novel kynurenic acid derivative on the nitroglycerin-induced calmodulin-dependent protein kinase II alpha (CamKIIalpha) and calcitonin gene-related peptide (CGRP) expression changes in the rat caudal trigeminal nucleus. BACKGROUND: Systemic administration of the nitric oxide donor nitroglycerin can trigger an attack in migraineurs. In the rat, nitroglycerin activates second-order neurons in the caudal trigeminal nucleus, and increases expression of the CamKIIalpha and decreases that of the CGRP there. As glutamatergic mechanisms may be crucial in trigeminal pain processing, the aim of our study was to examine the effects of L-kynurenine, a metabolic precursor of the N-methyl D-aspartate receptor antagonist kynurenic acid, on the nitroglycerin-induced changes in CamKIIalpha and CGRP immunoreactivity. METHODS: One hour before the nitroglycerin (10 mg/kg bodyweight, s.c.) injection, the animals were pretreated with L-kynurenine (300 mg/kg bodyweight, i.p.) or 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride (300 mg/kg bodyweight, i.p.), a novel kynurenic acid derivative. Four hours later, the rats were perfused transcardially and the cervical spinal cord segments were removed for immunohistochemistry. Results.- L-kynurenine and 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride pretreatment attenuated the nitroglycerin-induced changes in CamKIIalpha and CGRP immunoreactivity in the rat caudal trigeminal nucleus. CONCLUSIONS: These findings suggest a mechanism by which the inhibition of the excitatory amino acid receptors by kynurenic acid and its derivatives can alter trigeminal nociception.

Modulatory effects of probenecid on the nitroglycerin-induced changes in the rat caudal trigeminal nucleus.

Four hours after systemic administration of the nitric oxide donor nitroglycerin (10 mg/kg bodyweight, s.c.), the neurons of the rat caudal trigeminal nucleus are activated, the area covered by calcitonin gene-related peptide (CGRP)-immunoreactive fibres is decreased and the neuronal nitric oxide synthase (nNOS)- and the calmodulin-dependent protein kinase II alpha (CamKIIalpha)-immunopositive neurons in the same area are increased. Probenecid is a non-selective inhibitor of multidrug-resistance associated proteins and organic anion transporters thus it can modulate the transport functions in the central nervous system influencing nociception. Accordingly, the aim of the present experiments was to examine the effects of probenecid administration on the nitroglycerin-induced expressions of nNOS, CamKIIalpha and CGRP in the rat caudal trigeminal nucleus. Probenecid (200 mg/kg bodyweight, i.p.) pretreatment proved to mitigate the nitroglycerin-induced changes in expression in the rat caudal trigeminal nucleus. The data suggest that the changes caused by nitroglycerin in the expressions of CGRP, nNOS and CamKIIalpha can be influenced by probenecid modulating the inflammatory functions in the nervous system. These data may be of relevance for the pathogenesis of migraine headache.