BackgroundActivation 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.MethodsWe 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).ResultsLC-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).ConclusionsThese findings suggest that in migraine KYN is unidirectionally metabolized into ANA 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.

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The kynurenine pathway of tryptophan metabolism has been implicated in the pathophysiology of psychiatric disorders, including schizophrenia. We report here that the kynurenine metabolite, xanturenic acid (XA), interacts with, and activates mGlu2 and mGlu3 metabotropic glutamate receptors in heterologous expression systems. However, the molecular nature of this interaction is unknown, and our data cannot exclude that XA acts primarily on other targets, such as the vesicular glutamate transporter, in the CNS. Systemic administration of XA in mice produced antipsychotic-like effects in the MK-801-induced model of hyperactivity. This effect required the presence of mGlu2 receptors and was abrogated by the preferential mGlu2/3 receptor antagonist, LY341495. Because the mGlu2 receptor is a potential drug target in the treatment of schizophrenia, we decided to measure serum levels of XA and other kynurenine metabolites in patients affected by schizophrenia. Serum XA levels were largely reduced in a large cohort of patients affected by schizophrenia, and, in patients with first-episode schizophrenia, levels remained low after 12 months of antipsychotic medication. As opposed to other kynurenine metabolites, XA levels were also significantly reduced in first-degree relatives of patients affected by schizophrenia. We suggest that lowered serum XA levels might represent a novel trait marker for schizophrenia.

The relatively high proportion of IP changes in RR-MS patients seems to confirm our work hypothesis and warrants more work to confirm the result on a larger sample, and to understand the implications for related immunological disturbances and intestinal microbiota alterations. Our finding may also have relevance for oral treatments, recently introduced in clinical practice.

BackgroundThe reported efficacy of memantine in the treatment of patients with cluster headache (CH) suggests that NMDA receptors are involved in mechanisms of nociceptive sensitization within the trigeminal system associated with CH. NMDA receptors are activated or inhibited by neuroactive compounds generated by tryptophan metabolism through the kynurenine pathway. In the accompanying manuscript, we have found that serum levels of all kynurenine metabolites are altered in patients with chronic migraine. Here, we have extended the study to patients affected by episodic or chronic CH as compared to healthy controls.MethodWe assessed serum levels of kynurenine (KYN), kynurenic Acid (KYNA), anthranilic acid (ANA), 3-hydroxy-anthranilic acid (3-HANA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), quinolinic acid (QUINA), tryptophan (Trp) and 5-hydroxyindolacetic acid (5-HIAA) by means of a liquid chromatography/tandem mass spectrometry (LC/MS-MS) method in 21 patients affected by CH (15 with episodic and 6 with chronic CH), and 35 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded.ResultsLC/MS-MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-36 %), KYNA (-34 %), 3-HK (-51 %), 3-HANA (-54 %), XA (-25 %), 5-HIAA (-39 %) and QUINA (-43 %) in the serum of the overall population of patients affected by CH, as compared to healthy controls. Serum levels of Trp and ANA were instead significantly increased in CH patients (+18 % and +54 %, respectively). There was no difference in levels of any metabolite between patients affected by episodic and chronic CH, with the exception of KYN levels, which were higher in patients with chronic CH.ConclusionThe reduced levels of KYNA (an NMDA receptor antagonist) support the hypothesis that NMDA receptors are overactive in CH. A similar reduction in KYNA levels was shown in the accompanying manuscript in patients affected by chronic migraine. The reduced levels of XA, a putative analgesic compound, may contribute to explain the severity of pain attacks in CH. These data, associated with the data reported in the accompanying manuscript, supports a role for the kynurenine pathway in the pathophysiology of chronic headache disorders.

Background: Oftentimes, persistent post traumatic headache (PPTH) and migraine are phenotypically similar and the only clinical feature that differentiate them is the presence of a mild or moderate traumatic brain injury (mTBI). The aim of this study is to describe the differences in brain area and in biochemical cascade after concussion and to define the efficacy and safety of treatments in use. Methods: Sources were chosen in according to the International Classification of Headache Disorder (ICHD) criteria. Results: The articles demonstrated a significant difference between PPTH and migraine regarding static functional connectivity (sFC) and dynamic functional connectivity (dFC) in brain structure that could be used for exploring the pathophysiological mechanisms in PPTH. Many studies described a cascade of neuro-metabolic changes that occur after traumatic brain injury. These variations are associated to the mechanism occurring when developing a PPTH. Conclusions: The state of art of this important topic show how although the mechanisms underlying the development of the two different diseases are different, the treatment of common migraine is efficacious in patients that have developed a post traumatic form.

Migraine is one of the most common diseases in the world, with high economical and subjective burden. Migraine acute therapy is nowadays based on specific and non-specific drugs but up to 40% of episodic migraineurs still have unmet treatment needs and over 35% do not benefit from triptans administration. Serotonin-1F receptors have been identified in trigeminal system and became an ideal target for anti-migraine drug development as potential trigeminal neural inhibitors. Lasmiditan, a novel serotonin1F receptor agonist, showed specific affinity in vitro for the receptor without any vasoconstrictive action and inhibited markers associated with electrical stimulation of trigeminal ganglion in migraine animal models. Areas covered: This article reviews both preclinical and clinical studies on lasmiditan as a potential acute therapy for migraine, as well as pharmacokinetic and pharmacodynamic features. It also summarizes safety and tolerability data gathered in the various human studies. Expert opinion: The absence of vasoconstrictive effects makes lasmiditan a promising novel migraine acute therapy. Although preclinical and Phase I and II studies established a significant efficacy, the limited knowledge about pharmacokinetics and metabolism, the high rate of non-serious central nervous system side effects and the lack of larger studies remain still a matter of concern that should be addressed in future studies.

This study aims at determining serum levels of tryptophan and other metabolites of the kynurenine pathway in children with attention deficit hyperactivity disorder (ADHD) compared to healthy controls. Such metabolites interact with glutamate receptors in the central nervous system, potentially modulating mechanisms that are pivotal in ADHD and thus potentially representing peripheral biomarkers of the disorder. We measured serum levels of tryptophan and some metabolites of the kynurenine pathway in 102 children with ADHD and 62 healthy controls by liquid chromatography-tandem mass spectrometry (LC-MS/MS). As compared to healthy controls, children with ADHD showed a reduction in serum levels of anthranilic acid (-60%), kynurenic acid (-11.2%), and xanthurenic acid (-12.5%). In contrast, serum levels of tryptophan (+11.0%) and kynurenine (+48.6%) were significantly enhanced, and levels of quinolinic acid were unchanged in children with ADHD. In a logistic regression model, the presence of ADHD was predicted by low anthranilic acid and high tryptophan levels. These findings support the involvement of the kynurenine pathway in the pathophysiology of ADHD and suggest that anthranilic acid and tryptophan levels should be investigated as potential peripheral biomarker for ADHD.